Methods of making compositions comprising lecithin oils and NSAIDS for protecting the gastrointestinal tract and providing enhanced therapeutic activity

ABSTRACT

A novel pharmaceutical composition is provided by which nonsteroidal anti-inflammatory drugs (NSAIDs) are added directly to phospholipid-containing oil such as lecithin oils or to a bio-compatible oil to which an phospholipid has been added to make a NSAID-containing formulation that possess low gastrointestinal (GI) toxicity and enhanced therapeutic activity to treat or prevent inflammation, pain, fever, platelet aggregation, tissue ulcerations and/or other tissue disorders. The composition of the invention are in the form of a non-aqueous solution, paste, suspension, dispersion, colloidal suspension or in the form of an aqueous emulsion or microemulstion for internal, oral, direct or topical administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/433,454, having a 35 U.S.C. §371(c) date of Nov. 6, 2003, which is aU.S. national stage application of International Application No.PCT/US01/51605, filed on Dec. 19, 2001, which claims the benefit of U.S.Provisional Application No. 60/256,711 filed on Dec. 19, 2000. Therespective contents of each of these applications are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to unique compositions including abio-compatible oil and a non-steroidal anti-inflammatory drugs (NSAID),where the oil or a constituent thereof is effective in reducing GItoxicity of the NSAID and enhancing the drugs' therapeutic activity totreat inflammation, pain, fever and thrombosis as well as other diseasessuch as; stroke, traumatic brain injury, spinal chord injury,cardiovascular disease, ovarian cancer, colon cancer, Alzheimer'sdisease, arthritis, uveitis, and mucositis.

More particularly, the present invention relates to formulations inwhich a NSAID is admixed as a powder directly into a bio-compatible oilincluding a phospholipid to form a medication which can be a solution, apaste, a semi-solid, a dispersion, a suspension, a colloidal or mixturesthereof, where the medication can be administered internally, orallyand/or topically.

2. Description of the Related Art

NSAIDs constitute a family of compounds, the first of which to bediscovered being aspirin, that have the capacity to inhibit a number ofbiological pathogenic processes including; fever, inflammation, pain,thrombosis and carcinogenesis.¹ As a direct consequence of their greattherapeutic potential, NSAIDs are heavily consumed among the world'spopulace as both over-the-counter and prescription drugs. Because oftheir great utility, a significant percentage of our populace consumeNSAIDs with regularity including: the 30-40 millions. Americans who areafflicted with rheumatoid or osteoarthritis; and countless others thattake the medication to treat/prevent: inflammation and pain caused byother inflammatory conditions or injury, the pain of dysmenorrhea;fever; the development of thrombosis and related cardiovasculardiseases; ovarian cancer, colon cancer and Alzheimer's Disease.^(1,2)The problem with the trend of ever-increasing NSAID usage, especiallyamong the elderly, is that these drugs commonly induce gastrointestinal(GI) side-effects.³⁻⁶

In the stomach and small intestine the drugs cause dyspepsia (gastricdistress, heartburn, bloating or nausea), erosions, gastritis/duodenitisand ulcers in some individuals. Gastrointestinal bleeding may also occurin NSAID users that can result in episodes of anemia (of variableseverity), or hemorrhage—that may be life-threatening, in the mostserious cases.^(7,8) One or more of these GI complications have beenestimated to occur in 20-40% of regular NSAID users. Given the largeNSAID market, even infrequent GI complications send an estimated 76,000Americans to the hospital and kill estimated 7,600 annually.

One of the major contributions to the understanding of NSAID action camefrom the pioneering studies of Vane and associates in the early 1970'sthat reported that chemically dissimilar members of the NSAID familyshare the ability to inhibit the activity of the enzyme, cyclooxgenase(COX) that catalyzes the conversion of arachidonic acid to prostaglandinG₂ and H₂ by sequential steps of oxidation and peroxidation.⁹⁻¹¹Prostaglandin H₂ will then be converted to one of several eicosanoids ina target cell by a process catalyzed by specific prostaglandinsynthases. Thus, by reversibly or irreversibly inhibiting COX activity,NSAIDs could deplete a particular tissue or cellular fluid ofprostaglandins, which has been demonstrated to promote tissueinflammation.¹² Shortly after these revelations, Robert and hisassociates at the Upjohn Company demonstrated that certain classes ofprostaglandins shared the remarkable property of protecting the GIepithelium from a number of ulcerogenic compounds and/or conditions,demonstrating the “cytoprotective” nature of these lipid mediators.¹³Based upon these two major contributions, it was concluded that NSAIDsinduce injury and ulceration to the GI epithelium by inhibiting mucosalCOX activity and depleting the tissue of “cytoprotective”prostaglandins.

The next and most recent development in our understanding of arachidonicmetabolism came in the early 1990's, when a number of investigators¹⁴⁻¹⁸identified and cloned a second COX isozyme (now called COX-2), that wasstructurally and functionally related to the originally described enzyme(now called COX-1). In contrast to COX-1, which is constituitivelyexpressed in most tissues including the GI mucosa, COX-2 wasdemonstrated to be inducible, primarily by cytokines and other mediatorsof inflammation. Based on these findings, together with evidence thatCOX-2 is selectively expressed at sites of inflammation, and isexpressed at low or undetectable levels in non-inflamed GI mucosa,¹⁹⁻²³a number of pharmaceutical houses initiated the development of compoundsthat selectively inhibited COX-2.

This effort culminated in the launching of the first two COX-2 selectiveinhibitors, Celebrex (Celecoxib) and Vioxx (Rofecoxib). The pre-clinicaland clinical data released to date have indicated that these compoundsare therapeutically effective and have a low toxicity to the GI mucosa.This news has led to great excitement in both the medical and laycommunities, which has translated into record number prescriptions ofCelebrex and Vioxx being filled the first two years these drugs were onthe market.²⁴

A major concern of the inventor and a number of other investigatorsstudying NSAID-induced GI injury, is that the linkage between COXinhibition and GI injury and bleeding is not very strong. For example,Ligumsky and associates in the early 1980's published a series of papersin rats and dogs that appeared to dissociate COX inhibition from mucosalinjury.²⁵⁻²⁷ Initially they demonstrated that the aspirin and itsmetabolite, salicylic acid had equivalent ability to induce injury tothe canine gastric mucosa, even though aspirin depleted the tissue of“cytoprotective” prostaglandins, whereas salicylic acid displayed no COXinhibitory activity.²⁵ In subsequent rodent studies, it was demonstratedthat mucosal COX activity was inhibited by >90% regardless if aspirinwas administered subcutaneously or intragastrically, althoughulcerations only formed in the stomachs of rats when the NSAID wasadministered intragastrically.^(26,27) Whittle also reported adissociation between indomethacin's effect to induce COX inhibition andmucosal injury in the small intestine, as intestinal lesions only beginto develop 48 hrs after NSAID administration, at a time point where COXactivity (which is fully inhibited <3 hrs, post-indomethacin) hasreturned to normal.²⁸

It should be pointed out that the evidence suggesting that mucosal COXinhibition may not be directly involved in the pathogenesis ofNSAID—induced enteropathy—is also supported by some clinical studies,which have reported that i.v. administration of aspirin did not causedetectable histological injury to the human gastric mucosa, in contrastto oral administration of the NSAID.²⁹ It was also reported that after2-4 weeks of NSAID treatment the human gastric mucosa becomes resistantto the injurious actions of oral aspirin or indomethacin, and that thisadaptive response is not linked to a recovery of COX activity whichremains fully blocked during the study period.³⁰

Lastly, the hypothesis that NSAIDs induce GI injury, primarily byinhibiting mucosal COX-1 predicts that mice deficient in the isozyme,due to targeted gene disruption, would be prone to the development ofspontaneous mucosal ulcers and be more sensitive to NSAIDs than theirwild type littermates. Langenbach and associates³¹ have reported thatCOX-1 null animals have no detectable GI disease and if anything aremore resistant to indomethacin—induced ulcer development. To makematters more confusing, Morham et al.³² have reported in a subsequentstudy that COX-2 knockout mice are not viable and frequently succumb toperitonitis as well as renal disease. The possibility that COX-2inhibition may be detrimental, has also been supported by a number ofanimal studies that indicate that the healing of ulcers in the proximaland distal gut is exacerbated if animals are treated with selectiveCOX-2 blockers.^(33, 34) Similar complications in humans have not beenreported to date.

Based on the evidence documented above, a compelling case can be made toinvestigate, other mechanisms by which NSAIDs may induce GI mucosalinjury, and how this information can be used in the development ofalternative strategies to reduce or prevent the GI toxicity of thesecompounds. Other potential targets of NSAID—inducedgastro-enteropathy—are the ability of these drugs to: reduce mucosalblood flow and induce leukocyte adherence to the vascular wall; uncoupleoxidative phosphorylation; induce cellular acidification due to theirprotonophore characteristics; and to attenuate the hydrophobic,non-wettable characteristics of the mucosa, thereby increasing thetissue's susceptibility to luminal acid.³⁵⁻⁴⁰ It is this latter propertywhich has been the focus of the inventor's laboratory over the past15-20 years.

In 1983, the inventor's laboratory made the initial observation thatcanine gastric mucosa had a uniquely hydrophobic surface, as determinedby contact angle analysis.^(41, 42) Since then his and otherlaboratories have demonstrated that this non-wettable surface propertyof the gastric mucosa is found in a number of other species includingrodents and man.^(40,43,44) Furthermore, both biochemical andmorphological techniques were employed to demonstrate that this propertymay be attributable to an extracellular lining of surfactant-likephospholipid within and coating the mucus gel layer.⁴⁵⁻⁴⁷ The inventor'slaboratory also observed that many agents that damage the gastricmucosa, including NSAIDs, have the capacity to rapidly transform thetissue from a non-wettable (hydrophobic) to a wettable (hydrophilic)state, and that this injurious action could be attenuated by theadministration of synthetic or purified phospholipids.⁴⁸⁻⁵¹

In recent years, research has focused on the mechanism ofNSAID—phospholipid interaction. In these studies, the inventor'slaboratory have obtained compelling evidence that NSAIDs may inducemucosal injury by chemically associating with the zwitterionicphospholipids, such as phosphatidylcholine (PC) within and on thesurface of the mucus gel layer, with the site of electrostatic bindingbeing between the positively-charged choline head group of zwitterionicphospholipid, phosphatidylcholine (PC) and the negatively charged(carboxyl or sulfonyl) group of the NSAID.⁵² Based upon thisinformation, our group evaluated the GI toxicity of a number of NSAIDsthat were chemically pre-associated with synthetic or purified PC, priorto administration, and obtained evidence that these novel drugs were farless injurious, with regards to GI lesion formation and bleeding thanthe unmodified NSAIDs, in the rat. The applicability of this approach tohuman disease was recently confirmed when pilot clinical studiesrevealed that PC—aspirin, employing purified (93% pure) PC, inducedsignificantly fewer gastric lesions in human subjects than unmodifiedaspirin over a 4 day period, in a pilot double blind, cross-overstudy.⁵³

Interestingly, the inventor's laboratory also determined that PC—NSAIDshave superior therapeutic efficacy and potency to the unmodified drugsin animal models of fever, inflammation/pain, thrombosis andosteoporosis indicating that their lower gastric toxicity could not besimply explained by a reduction in bioavailability.^(52, 54)

Although the combination of PC (other of similar phospholipids) andNSAIDs result in reduced pathogenic effects of NSAID administration,oral administration of these combinations have been less than adequatebecause the combination requires a larger volume per effective dose thanNSAID alone. Thus, there is a need in the art for a composition of NSAIDand carrier that allows for increased NSAID concentration in thecomposition and where the carrier reduces the pathogenic effects ofNSAIDs and is in a form that is amenable to administration orally,internally or topically. Moreover, there is a need in the art for anNSAID composition which has improved self-life, especially foraspirin-containing medicaments.

SUMMARY OF THE INVENTION

General Compositions

The present invention provides a composition including a relatively highconcentration of a non-steroidal anti-inflammatory drugs (NSAID) in anon-aqueous, fluid carrier.

The present invention provides a composition of an NSAID in non-aqueous,fluid carrier, where the carrier comprises a bio-compatible oil and aphospholipid.

The present invention provides a composition of an NSAID in non-aqueous,fluid carrier, where the carrier comprises a phospholipid richbio-compatible oil.

The present invention also provides a composition including a relativelyhigh concentration of an NSAID in a non-aqueous, fluid carrier, wherethe carrier or constituents thereof act to reduce the pathogenic effectsof the NSAID, to increase the bioavailability of the NSAID, and toincrease NSAID availability across relatively hydrophobic barriers in ananimal including a human.

The present invention also provides a composition including a relativelyhigh concentration of an NSAID, a phospholipid in a non-aqueous, fluidcarrier, where the phospholipid is present in an amount sufficient toreduce the pathogenic effects of the NSAID, to increase thebioavailability of the NSAID, and to increase NSAID availability acrossrelatively hydrophobic barriers in an animal including a human.

The present invention provides a composition including a relatively highconcentration of an NSAID in a non-aqueous, fluid carrier comprising aphospholipid and a bio-compatible oil, where the phospholipid is presentin an amount sufficient to reduce the pathogenic effects of the NSAID,to increase the bioavailability of the NSAID, and to increase NSAIDavailability across relatively hydrophobic barriers in an animalincluding a human.

The presence of the phospholipid also reduces general pathogenic and/ortoxicity of the NSAID. Thus, the phospholipid reduce and/or preventliver damage due to the administration of acetaminophen and/or kidneyand/or cardiovascular side-effect due to the administration of otherNSAIDs such as ibuprofen or the COX-2 inhibitors.

General Methods for Making the General Compositions

The present invention also provides a method of preparing a compositioncomprising an NSAID in a non-aqueous, fluid carrier comprising the stepof combining the NSAID with the carrier to form a solution, a paste, asemi-solid, a dispersion, a suspension, a colloidal suspension or amixture thereof.

The present invention also provides a method of preparing a compositioncomprising an NSAID in a non-aqueous, fluid carrier including aphospholipid comprising the step of combining the NSAID with the carrierto form a solution, a paste, a semi-solid, a dispersion, a suspension,colloidal suspension or mixtures thereof comprising phospholipid-NSAIDassociation complex.

The present invention also provides a method of preparing a compositioncomprising an NSAID in a non-aqueous, fluid carrier including aphosphatidylcholine-containing bio-compatible oil comprising the step ofcombining the NSAID with the carrier to form a solution, a paste, asemi-solid, a dispersion, a suspension, a colloidal suspension or amixture thereof comprising phosphatidylcholine-NSAID associated complex.

The present invention also provides a method of preparing a compositioncomprising an NSAID in a non-aqueous, fluid carrier comprising the stepof combining the NSAID with the carrier to form a solution, a paste, asemi-solid, a dispersion, a suspension, a colloidal suspension or amixture thereof where the carrier comprises a phospholipid-containingbio-compatible oil or a bio-compatible oil and a phospholipid or amixture thereof.

Emulsified Compositions

The present invention also provides an aqueous emulsion of a compositionincluding a non-aqueous carrier, where the carrier includes abio-compatible oil, a phospholipid in an amount sufficient to produce atherapeutically beneficial effect and zero to a therapeuticallyeffective amount of an NSAID and when the NSAID is present, the amountof phospholipid is also sufficient to reduce the pathogenic effects ofthe NSAID. The aqueous emulsion can also include bio-compatibleemulsifying agents to maintain the composition in a state of emulsionfor extended periods of time. Preferably, a particle size of theemulsified composition is sufficiently small to allow the composition tobe taken orally or to be injected into a tissue or organ site withoutcausing adverse effect. For i.v. or i.a. injectable forms,microemulsions are preferred, where the average particle size can bereduced to between 0.5 and about 10 μm, and preferably, between about 1and 5 μm.

The present invention also provides an aqueous microemulsion of acomposition including an non-aqueous carrier, where the carrier includesa bio-compatible oil, a phospholipid in an amount sufficient to producea therapeutically beneficial effect and zero to a therapeuticallyeffective amount of a NSAID and when the NSAID is present, the amount ofphospholipid is also sufficient to reduce the pathogenic effects of theNSAID. The aqueous emulsion can also include bio-compatible emulsifyingagents to maintain the composition in a state of emulsion for extendedperiods of time.

Method for making Emulsified Compositions

The present invention also provides a method for preparing an aqueousemulsion of this invention including the step of adding a given amountof a desired non-aqueous composition of this invention to an aqueoussolution in the absence or presence of an emulsifying agent and mixingthe composition and the solution for a time sufficient to form anemulsion, where the emulsifying agent, when present, is present in anamount sufficient to form a stable emulsion.

The present invention also provides a method for preparing an aqueousmicroemulsion of this invention including the step of adding a givenamount of a desired non-aqueous composition of this invention to anaqueous solution in the absence or presence of an emulsifying agent,mixing the composition and solution for a time sufficient to form anemulsion, and shearing the emulsion under microemulsifying conditions toform a microemulsion, where the emulsifying agent, when present, ispresent in an amount sufficient to form a stable microemulsion.

The reason the emulsifying agent is optional is because the phospholipidthemselves have some emulsifying properties.

Compositions for Treating Inflamation

The present invention also provides a composition for reducing tissueinflamation including a non-aqueous carrier including a therapeuticallyeffective amount of an NSAID and a sufficient amount of a phospholipidto reduce the pathogenic effects of the NSAID, where the compositionreduces tissue inflammation at an NSAID dose below a dose typicallyrequired to illicit the same therapeutic response in the absence of thephospholipid with decreased mucosal toxicity and/or irritation.

The present invention also provides a after surgical treatment forreducing tissue, organ and/or incision inflammation and otherconsequences thereof, where the composition includes a non-aqueouscarrier including a therapeutically effective amount of an NSAID and asufficient amount of a phospholipid to reduce the pathogenic effects ofthe NSAID or where the composition includes or an aqueous solution intowhich the non-aqueous carrier composition is dispersed (e.g., anemulsion or microemulsion), where the composition reduces tissueinflammation at an NSAID dose below a dose typically required to illicitthe same therapeutic response in the absence of the phospholipid withdecreased mucosal toxicity and/or irritation. Of course, the compositioncan be an ointment, a spray, coated on a wipe, coated on a biodegradablesubstrate or the like.

Composition for Treating Platelet Aggregation

The present invention also provides a composition for reducing plateletaggregation including a non-aqueous carrier including a therapeuticallyeffective amount of an NSAID and a sufficient amount of a phospholipidto reduce the pathogenic effects of the NSAID or an aqueous solutioninto which the non-aqueous carrier composition is dispersed (e.g., anemulsion or microemulsion), where the composition reduces plateletaggregation at an NSAID dose below a dose typically required to illicitthe same therapeutic response in the absence of the phospholipid withdecreased mucosal toxicity and/or irritation.

Composition for Treating Pyretic Conditions

The present invention also provides a composition for anti-pyreticactivity including a non-aqueous carrier including a therapeuticallyeffective amount of an NSAID and a sufficient amount of a phospholipidto reduce the pathogenic effects of the NSAID or an aqueous solutioninto which the non-aqueous carrier composition is dispersed (e.g., anemulsion or microemulsion), where the composition has anti-pyreticactivity at an NSAID dose below a dose typically required to illicit thesame therapeutic response in the absence of the phospholipid withdecreased mucosal toxicity and/or irritation.

Composition for Treating Ulcerated Tissues

The present invention provides a composition for treating ulceratedtissues including an aqueous emulsion or microemulsion comprising aphospholipid, a bio-compatible oil and zero to a therapeuticallyeffective amount of an NSAID or a non-aqueous including comprising aphospholipid, a bio-compatible oil and zero to a therapeuticallyeffective amount of an NSAID, where the phospholipid is present in asufficient amount to reduce tissue ulceration and the NSAID, whenpresent, reduces inflammation of the ulcerated regions of the tissue.

Compositions for Treating Oral Ulcerations

The present invention also provides a mouth wash including an aqueousemulsion or microemulsion comprising a phospholipid, a bio-compatibleoil and zero to a therapeutically effective amount of an NSAID, wherethe phospholipid is present in a sufficient amount to reduce mouthulceration and the NSAID, when present, reduces inflammation of theulcerated regions of the mouth and the amount of phospholipid issufficient not only to reduce mouth ulceration, but is also sufficientto reduce or present NSAID induced tissue damage.

Compositions for Treating Oral, Esophagus and GI Tract Ulcerations

The present invention also provides a drinkable medication including anaqueous emulsion or microemulsion comprising a phospholipid, abio-compatible oil and zero to a therapeutically effective amount of anNSAID, where the phospholipid is present in a sufficient amount toreduce mouth, esophagus, and/or GI tract ulceration and the NSAID, whenpresent, reduces inflammation of the ulcerated regions of the mouth,esophagus and/or GI tract, and the amount of phospholipid is sufficientnot only to reduce mouth, esophagus and/or GI tract ulceration, but isalso sufficient to reduce when present NSAID induced tissue damage.

Composition for Treating Eye Inflammation

The present invention also provides eye drops including an aqueousemulsion or microemulsion comprising a phospholipid, a bio-compatibleoil and zero to a therapeutically effective amount of an NSAID in anaqueous solution, where the phospholipid is present in a sufficientamount to reduce eye inflammation and/or ulceration or irritation andthe NSAID, when present, reduces inflammation of the scleral, uveal,lens or chorio-retinal regions of the eye, and the amount ofphospholipid is sufficient not only to reduce eye inflammation, but isalso sufficient to reduce or present NSAID induced tissue damage.

Methods for Treating Ulcerated Tissues

The present invention also provides methods for treating inflammationand/or ulceration disorders of the mouth, esophagus, GI tract, and/oreye via the administration of an emulsion or microemulsion of thisinvention.

Composition for Treating Central and/or Peripheral Nerve System Traumas

The present invention also provides a composition for orally orinternally treating spinal cord, stroke and/or traumatic brain injuries,where the composition includes a non-aqueous carrier including aphospholipid and a therapeutically effective amount of an NSAID or anon-aqueous including comprising a phospholipid, a bio-compatible oiland zero to a therapeutically effective amount of an NSAID, where thephospholipid increases transport of the NSAID across the blood-brainbarrier or into the central nervous system (CNS) or peripheral nervoussystem (PNS) allowing more NSAID to get to the trauma site and reduceinflammation, where NSAID reduces inflammation, platelet aggregation,pain (nociceptive) sensation, cell death and/or apoptosis due toinflammation.

Methods for Treating Central and/or Peripheral Nerve System Traumas

The present invention also provides methods for treating spinal cord,stroke and/or traumatic brain injuries by orally administering and/ordirectly administering via injection a composition of this invention,where the direct administration can be either into a vein (i.v.administration), an artery (i.a. administration) or directly into thetrauma site (direct administration), where the phospholipid increasestransport of the NSAID across the blood-brain barrier allowing moreNSAID to get to the trauma site and reduce inflammation for i.v. andi.a. administration and the phospholipid reduces the pathogenic effectsof the NSAID in all administration formats.

The present invention also provides a medication for amelioratingsymptoms of spinal chord injury (e.g., chronic pain syndrome), strokeand/or traumatic brain injury, where the medication is an aqueousemulsion or microemulsion including a relatively high concentration ofan NSAID in an oil based carrier including a phospholipid, where theNSAID and the phospholipid form an association complex in themedication, where the composition include a sufficient concentration ofthe NSAID to reduce swelling of the traumatized tissue and a sufficientconcentration of the phospholipid to reduce the pathogenic effects ofthe NSAID on the traumatized tissue.

Composition for Treating Alzheimer's Disease

The present invention also provides a composition for preventing,treating or ameliorating the symptoms associated with Alzheimer'sdisease including a bio-compatible oil, a phospholipid and atherapeutically effective amount of an NSAID, where the NSAID and thephospholipid act to prevent the onset of the symptoms of Alzheimer'sdisease or ameliorate the symptoms of Alzheimer's disease.

Methods for Treating Alzheimer's Disease

The present invention also provides a method for preventing, treating orameliorating the symptoms associated with Alzheimer's disease includingthe step of orally or internally administering a composition of thisinvention orally and/or internally according to a treatment protocol.

DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdetailed description together with the appended illustrative drawings inwhich like elements are numbered the same:

FIG. 1 demonstrates that in contrast to the high number of gastriclesions observed in rats administered aspirin (ASA) alone, rats treatedwith all three aspirin:lecithin (LEC, using the lecithin oil, Phosal 35SB) formulations having a ASA:LEC weight ratio of about 1:0.5, 1:1 andabout 1:2 had significantly fewer gastric lesions;

FIG. 2 demonstrates that indomethacin, at a dose of 10 mg/kg, induces asevere increase in GI bleeding that is markedly and significantlyreduced in rats that were intragastrically administered an equivalentdose of indomethacin in combination with Phosal 35 SB, at aNSAID:lecithin weight ration of 1:1;

FIG. 3 demonstrates that ibuprofen (which is considered one of the leasttoxic of the conventional NSAIDs in rats), at a dose of 100 mg/kginduces a modest increase in GI bleeding that is significantly reducedin rats that were intragastrically administered an equivalent dose ofibuprofen in combination with Phosal 35 SB, at a NSAID:lecithin weightratio of 1:1;

FIG. 4 demonstrates that aspirin, at a dose of 10 mg/kg, had a modestability to increase the pain threshold of the rats' affected paw,whereas the analgesic activity of an equivalent dose of aspirin, whenadministered in combination with the lecithin oil, at all weight ratiostested, was significantly enhanced;

FIG. 5 demonstrates that ibuprofen, at a dose of 25 mg/kg, has a modestthough non-significant, ability to increase the pain pressure thresholdof the rats' inflamed paw, whereas the analgesic activity of anequivalent dose of ibuprofen, when administered in combination with thelecithin oil at a weight ratio of 1:1, was significantly enhanced;

FIG. 6 demonstrates that indomethacin, at a dose of 4 mg/kg, has amodest though non-significant, ability to increase the pain pressurethreshold of the rats' inflamed paw, whereas the analgesic activity ofan equivalent dose of indomethacin, when administered in combinationwith the lecithin oil at a weight ratio of 1:1, was significantlyenhanced;

FIG. 7A graphically depicts data relating to hyper-algesia induced bySpinal Cord Injury (SCI) is reversed by treatment with PC-Ibuprofen andIbuprofen;

FIG. 7B graphically depicts data relating to hyper-algesia induced bySpinal Cord Injury (SCI) is reversed by treatment with PC-Ibuprofen andIbuprofen;

FIG. 8 graphically depicts data relating to analgesic activity ofPC-Ibuprofen and Ibuprofen in rats 5 week after spinal cord injury;

FIG. 9 graphically depicts data relating to body weight gain over 6 weekperiod in Spinal Cord Injured rats treated with PC-Ibuprofen andIbuprofen;

FIG. 10 graphically depicts data relating to recovered motor functionafter Spinal Cord Injury (SCI) treated with PC-Ibuprofen and Ibuprofen;

FIG. 11 graphically depicts the PC-aspirin complex significantly reducedthe number of gastric erosions by 70% in susceptible individuals incomparison to an equivalent dose of unmodified aspirin and thisreduction in gastric toxicity did not relate to an alteration in the COXinhibitory activity of the drug;

FIG. 12 graphically depicts that both aspirin and PC-aspirin had anequivalent ability to inhibit antral COX activity by >85%;

FIG. 13A graphically depicts Concentration of TXB₂ in rat platelets, 30min after oral administration of saline, DPPC, ASA (20 mg/kg), or ASAcomplexed with DPPC. PRP was prepared and aggregation induced by AA (2mM). TXB₂ was measured by RIA. The results expressed as mean±SEM; n=3.*=p<0.050 vs ASA—Abbreviations: DPPC=dipalmitoylphosphatidylcholine;AA=arachidonic acid; pRP=platelet rich plasma; TXB=thromboxane;

FIG. 13B graphically depicts the effect of intragastric administrationto rats of 20 mg/kg ASA alone or complexed with DPPC on 6KPGF1aproduction by abdominal aorta. After 1 hr the aorta was removed and eachaorta ring was incubated at 370 C for 10 min in Tris-HCl buffercontaining 25 mM AA. 6KPGF1a was measured by RIA. *=p<0.050 vs ASA;**=p<0.001 vs saline; n=4;

FIG. 14A graphically depicts the representative recording of the bloodflow velocities (kHz) from a rabbit during thrombus formation given with2.5 mg/kg of unmodified aspirin or aspirin complexed to DPPC along withsaline or PC controls;

FIG. 14B graphically depicts the effect of 2.5 mg/kg aspirin with orwithout DPPC on the thrombus wt. in a rabbit arterial thrombosis model.*=p<0.001 vs ASA;

FIG. 14C graphically depicts the effect of 2.5 mg/kg aspirin with orwithout DPPC on the PGI2 to TXA2 ratio of carotid artery of rabbitarterial thrombosis model; and

FIG. 15 graphically depicts data relating to liver injury in rats, asindicated by elevations in the plasma levels of the enzyme aspartatetransaminase (AST), 24 hours after fasted rats are orally administratedacetaminophen (800 mg/kg) alone or in combination with P35SB at wt.ratios of 1:1 and 1:2.

DEFINITIONS OF TERMS

The following terms will have the meanings set forth below, which may ormay not correspond to their generally accepted meaning:

The term “NSAID” means any variety of drugs generally classified asnonsteroidal anti-inflammatory drugs, including, without limitation,ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin,diclofenac, acetaminophen, COX2 inhibitors or any mixture thereof.

The term “essentially free” means compositions that include a giveningredient in an amount that is biologically inert and/or not an active,preferably, the component is present in an amount less than about 0.10wt. % of a given ingredient, and particularly in an amount less thanabout 0.01 wt. % being preferred.

The term “relatively high concentration” means that the weight ratio ofNSAID to carrier is from about 10:1 to about 1:10. Preferably, theweight ratio of NSAID to carrier is from about 5:1 to about 1:5,particular, from about 2:1 to 1:2, and especially from about 2:1 to 1:1.

The term zwitterionic phospholipid embraces a wide range ofphospholipids, including but not limited to phosphatidylcholine,phosphatidylserine, phosphalidylethanolamine, sphingomyelin and otherceramides, as well as various other zwitterionic phospholipids.

The term “bio-compatible oil” means any oil that has been approved forhuman consumption by the FDA or animal consumption.

The term “internal administration” or “internally administered” meansadministration via any technique that present a composition directlyinto the blood stream, a tissue site, an organ or the like without firstpassing through the digestive tract.

The term “oral administration” or “oral administered” meansadministration via mouth.

The term “topical administration” or “topically administered” meansadministration onto a surface such as the skin, a mucosal gel layer, theeye, a tissue and/or organ exposed during a surgical procedure, or anyother exposed bodily tissue.

The term “association complex” means a non-covalent chemical and/orphysical interaction between an NSAID and a phospholipid such as theinteraction between an NSAID and a zwitterionic phospholipid.

The term “zwitterionic” means that a molecule includes both a positivelycharged and a negatively charged functional group at biological pHs.

The term “anionic phospholipid” means a phospholipid which has anoverall negative charge at biological pHs.

The term “neutral lipid” means a non-charged lipid.

The term “emulsion” means the suspension of one immiscible phase inanother immiscible phase in the form of small droplets of the firstphase in the second phase. As used herein, the term emulsion includessuspension that separate quickly or not at all, and, therefore, includesstable and non-stable emulsions.

The term “stable emulsion” means a oil in water mixture that does notseparate for at least one day after preparation, preferably does notseparate for at least one week, particularly does not separate after atleast one month and especially remains in an emulsion indefinitely.

The term “stable microemulsion” means a oil in water mixture that doesnot separate for at least one day after preparation, preferably does notseparate for at least one week, particularly does not separate after atleast one month and especially remains in an emulsion indefinitely.

The term “relatively hydrophobic barriers” means any external, internal,cellular or sub-cellular barrier which has hydrophobic properties, whichgenerally resists or reduces transport of hydrophilic reagents acrossthe barrier. Such barriers include, without limitation, a mucosal gellayer, a plasma lemma (cellular membrane), the blood-brain barrier, orany other barrier of an animal including a human, which more easilytransports hydrophobic materials therethrough than hydrophilicmaterials.

DETAILED DESCRIPTION OF THE INVENTION

The inventor has found that unique pharmaceutical formulationscontaining a non-aqueous, fluid bio-compatible carrier including aphospholipid and optionally a NSAID can be prepared to improve therepair of mucosal tissue ulceration and/or decrease pathogenic effectsof NSAID administration. When the NSAID is present, a weight ratio ofNSAID to carrier is generally from about 10:1 to about 1:10, whichresults in highly concentrated mixture of the NSAID in the carrier thathave unexpected properties of low GI toxicity and enhanced therapeuticactivity for the NSAID. Preferably, the weight ratio of NSAID to carrieris from about 5:1 to about 1:5, particular, from about 2:1 to 1:2, andespecially from about 2:1 to 1:1.

For composition including an NSAID, this invention has been reduced topractice in rodent models of NSAID-induced ulcer disease, and acuteinflammation of the hindpaw. The formulations can be in the form of asolution, a paste, a semi-solid, a dispersion, a suspension, a colloidalsuspension or a mixture thereof.

For composition that do not include an NSAID, the phospholipid itselfmay impart a therapeutically beneficial effect in preventing and/orreducing ulcerations in tissues, especially tissue ulceration caused byradiotherapy and/or chemotherapy.

The non-aqueous, fluid bio-compatible carrier comprises a bio-compatibleoil or mixture of bio-compatible oils or oil like substances. Thebio-compatible oil or oil mixture can either naturally include aphospholipid or has had a phospholipid added thereto. The amount ofphospholipid present naturally or via addition to the carrier issufficient of prevent, reduce or treat ulceration of tissues or, whenthe formulation includes an NSAID, is sufficient to reduce thepathogenic effects of the NSAID, such as GI ulceration, bleeding, liverdamage, kidney damage, and/or cardiovascular disease and/or side-effectssuch as; high blood pressure, atherosclerosis, thrombosis, anginapectoralis, strokes and myocardial infarction.

The inventor has also found that an aqueous emulsion or microemulsion ofthe above compositions can be formed to treat mouth, esophagus and GIulceration resulting form or caused by radiotherapy and/or chemotherapyof various forms of cancer. The emulsion or microemulsion can either beadministered after, during, prior to or can be administered in a mixedprotocol including administration prior to, during and/or afterradiotherapy and/or chemotherapy.

In previous publications and patents both by the inventor and others,compositions including a phospholipid and an NSAID were formed either byinitially dissolving the components in an organic solvent, such asmethanol, ethanol or chloroform, and removing the solvent bydistillation or evaporation; or the NSAID was dissolved in an aqueoussolution to which the phospholipid was added, followed bylyophilization. These processes allow the two components to chemicallyinteract to form a complex. These processes most often used aphosphatidylcholine (PC) as the phospholipid either syntheticallyprepared such as dipalmitoylphosphatidylcholine (DPPC) or as a purifiedor semipurified compound.

The present invention relates broadly to a pharmaceutical formulation orcomposition including a non-aqueous, fluid carrier including aphospholipid and optionally an NSAID, where the phospholipid is in anamount sufficient to prevent, reduce or treat tissue ulceration and/orinflammation, and when an NSAID is present, and the phospholipid ispresent in the amount capable of reducing the pathogenic effects of theNSAID. The formulations are generally viscous solutions, pastes,semi-solids, dispersions, suspensions, colloidal suspension or mixturesthereof and are capable of being orally administered, directlyadministered, internally administered or topically administered.

The present invention relates broadly to a pharmaceutical formulation orcomposition including a non-aqueous, fluid carrier including aphospholipid and an NSAID, where the phospholipid is in an amountsufficient to prevent, reduce or treat tissue ulceration, and to reducethe GI toxicity of the NSAID. The use of a non-aqueous, fluid allows theformation of compositions having high concentrations of the NSAID toreduce a volume of an effective therapeutic amount of the NSAID. Theformulations are generally viscous solutions, pastes, semi-solids,dispersions, suspensions, colloidal suspension or mixtures thereof andare capable of being orally administered, internally administered ortopically administered.

The present invention also relate broadly to a method of preparing thepharmaceutical formulations including the step of combining a solidNSAID with a non-aqueous carrier, where the carrier includes aphospholipid-containing bio-compatible oil or a bio-compatible oil and aphospholipid, or mixtures thereof, to form a highly concentrated NSAIDcomposition with reduced NSAID pathogenic effects.

The present invention also broadly relates to a method for treatinginflammation, pain or other NSAID treatable pathologies by administeringan effective amount of a pharmaceutical formulation including anon-aqueous, fluid carrier including an NSAID and a phospholipid, wherethe phospholipid is present in an amount sufficient to reduce NSAIDpathology and the NSAID is present in a therapeutically effectiveamount, where the phospholipid-NSAID combination allows the amount ofNSAID administered per dose to be less than an equivalent amount ofNSAID in the absence of the phospholipid to illicit the same therapeuticeffect.

The present invention also broadly relates to a method for preventing,reducing and/or treating ulcerated tissue and/or reducing inflammation,pain or other NSAID treatable pathologies associated with tissueinflammation and/or ulceration by administering an effective amount of apharmaceutical formulation including a phospholipid and optionally anNSAID in a non-aqueous carrier, where the carrier is a bio-compatibleoils or mixture thereof.

In particular, the inventor has found that unique pharmaceuticalformulations containing a bio-compatible oil including a phospholipidsuch as non-purified lecithin oils which naturally includes aphospholipid and where the resulting formulation represent a solution, apaste, a semi-solid, a dispersion, a suspension, colloidal suspension ormixtures thereof or composition with unexpected properties of low GItoxicity and enhanced therapeutic activity.

The compositions are easily prepared by combining a bio-compatible oiland a phospholipid and optionally an NSAID, where the NSAID is added asa powder directly into a crude or semi-crude lecithin oil to form apaste, semi-solid, dispersion or colloidal suspension or similarcomposition that can be added to soft or hard gelatin capsules orvegicaps available from VitaHerb Nutraceuticals of Placentia, Calif. fororal administration, injected for internal administration or applied tothe skin for topical administration. An unexpected observation was thatthis simple formulations, similar to PC-NSAID products that are made bythe conventional methods described above, have markedly lowgastrointestinal (GI) toxicity in rodent models of NSAID-induced ulcerdisease as shown in FIGS. 1, 2 & 15, and also have enhanced therapeuticactivity to treat inflammation/pain in an acute model of pawinflammation as shown in FIGS. 3 & 4, and chronic models of spinal chordinjuries as shown in FIGS. 7 & 8.

Generally, the weight ratio of NSAID to a phospholipid-containing oilranges from about 10:1 to about 1:10, preferably, from about 4:1 toabout 1:4, particularly, from about 2:1 and about 1:2, and especially,from about 2:1 to about 1:1. For oils useful in the practice of thisinvention that naturally contain a phospholipid, the oils generallyinclude from about 10 to about 15 wt. % of a phospholipid, preferably,from about 10 wt. % to about 20 wt. % of a phospholipid, andparticularly, from about 10 wt. % to about 40 wt. % of a phospholipid.However, greater and lesser amounts of a phospholipid can be used aswell. However, at wt. % much below about 10 wt. %, an effectivetherapeutic amount or sufficient amount to associate with any addedNSAID becomes a concern, while at wt. % higher than about 40 wt. %, apurified phospholipid may have to be added to bio-compatible oils thatnaturally include a phospholipid such as lecithin oil. Forbio-compatible oils that contain either low amount of a phospholipid(less than about 10 wt. %), a phospholipid is added to the oil. Suchoil-phospholipid combination can be prepared with phospholipidconcentrations as high as about 90 wt. %. However, preferred combinationinclude phospholipid amounts of between about 10 wt. % and about 90 wt.%, particularly between about 20 wt. % and about 80 wt. %, moreparticularly, between about 20 wt. % and about 60 wt. % and especially,between about 20 wt. % and about 40 wt. %.

Generally, the dose of NSAID containing compositions of this inventionfor general use ranges from 5 mg per dose to 500 mg per dose. Of course,smaller and higher dose formulations can be prepared; however, this doesrange encompasses the ranges typically encountered for NSAIDscommercially available. Preferably, the NSAID dose range is from about10 mg to about 325 mg per dose, particularly, from about 25 mg to about200 mg per dose and especially from about 50 mg to about 100 mg perdose. It should be recognized that each NSAID has a different dose rangeper tablet or the like, and these ranges are meant to encompasses allranges that a patient would generally encounter when taking formulationscontaining an NSAID as that term is used herein. It should also berecognized that the composition of this invention do not just include anNSAID, but include an NSAID in a non-aqueous, fluid carrier including aphospholipid, where the amount of phospholipid is sufficient, when anNSAID is present, to enhance the therapeutic efficacy of the NSAID,while reducing NSAID pathogenic effects. These NSAID pathogenic effectsare, of course, NSAID specific, but include, without limitation, GIdamage such as ulceration, bleeding or the like (most, if not allNSAIDs), liver damage (e.g., acetaminophen), kidney damage (e.g.,ibuprofen, acetaminophen, COX-2 inhibitors), heart damage (e.g., COX-2inhibitors), etc. Because NSAID-phospholipid associated complexes, themg dose of NSAID needed to illicit a given therapeutic effect orresponse (fever reduction, reduction in inflammation, reduction inplatelet aggregation, etc.) is reduced. The reduction can be range froma 1 fold reduction in mg dose to a 15 fold reduction in mg dose.Preferably, the range is from about a 1 fold reduction to about a 10fold reduction in mg NSAID dose. The increased bio-activity afforded bya composition including phospholipid-NSAID combination does not resultin an equivalent increase in toxicity of the NSAID, but surprisinglyresults in a decreased toxicity of the NSAID as evidenced by the datapresent herein.

For more severe condition such as arthritis, Alzheimer's disease, CNSand PNS trauma, or other more severe condition treatable with NSAIDsand/or phospholipids, the NSAID daily dose requirements are generallymuch higher. Typically, the daily dose ranges from about 100 mg to about5000 mg per day, preferably, from about 500 mg to about 3000 mg per day,particularly, from about 750 mg to about 3000 mg per day and especiallyfrom about 1000 mg to about 3000 mg per day. Again, the enhancedefficacy of phospholipid-NSAID combinations allow the dose to illicit agreater therapeutic effect, without concurrent increase in pathogenic ortoxicity of the NSAID. Of course, this enhancement in bio-activity ofthe NSAIDs allows lower doses of the NSAIDs to be administered.

As a general rule of thumb, when administering an NSAID in a formulationof this invention, where the NSAID is dissolved, dispersed, suspended orotherwise mixed into a non-aqueous carrier, a bio-compatible oil,including a sufficient amount of a phospholipid to enhance NSAIDactivity, while reducing NSAID toxicity, the dosage requirements canfrom as low as 5% of the recommended dose needed to treat a specificcondition to 100% of that dose depending on the patient, the conditionand other factors. Preferably, the dosage is from about 10% to about 90%of the recommended dose needed to treat a specific condition andparticularly from about 10% to about 50% of the recommended dose neededto treat a specific condition. The recommended dosage requirements for agiven NSAID for a given condition can be found in such publication asthe Physicians Desk Reference (PDR), AMA publication, FDA publication orthe like, and are well established criteria.

The compositions of this invention can also include: (1) apharmaceutically acceptable amount of antioxidant selected from thegroup consisting of Vitamin A, Vitamin C, Vitamin E or otherantioxidants approved for human and animal consumption by the FDA andmixtures or combinations thereof; (2) a pharmaceutically acceptableamount of a polyvalent cation selected from the group consisting ofcopper, zinc, gold, aluminum and calcium and mixtures or combinationsthereof; (3) a pharmaceutically acceptable amount of an agent to promotefluidity, spreadability or permeability selected from the groupconsisting of dimethylsulfoxide/DMSO, propylene glycol/PPG, and mediumchain triglyceride/MCT and mixtures or combination thereof; (4) apharmaceutically acceptable amount of a food coloration or non-toxicdye; (5) a pharmaceutically acceptable amount of a flavor enhancer; (6)an excipient; and/or (7) an adjuvant.

General Compositions

The present invention relates to a composition including a relativelyhigh concentration of a non-steroidal anti-inflammatory drugs (NSAID) ina non-aqueous, fluid carrier. Preferably, the carrier comprises abio-compatible oil and a phospholipid or a phospholipid richbio-compatible oil. The carrier either naturally and/or via additionincludes a sufficient amount phospholipid to reduce pathogenic affectsof the NSAID, to increase a bioavailability of the NSAID and to increaseNSAID availability across relatively hydrophobic barriers in an animal'sbody including a human's body. Preferably, the resulting compositionincludes a relatively high concentration of a phospholipid-NSAIDassociation complex. Particularly, the resulting composition includes arelatively high concentration of a phosphatidylcholine-NSAID associatedcomplex.

The present invention relates to a composition including a relativelyhigh concentration of an NSAID in a non-aqueous, fluid carriercomprising a phospholipid and a bio-compatible oil, where thephospholipid is present in an amount sufficient to reduce pathogenicaffects of the NSAID, to increase the bioavailability of the NSAID andto increase NSAID availability across relatively hydrophobic barriers inan animal's body including a human body, where the composition dose issufficient to result in the delivery of a therapeutical effective amountof the NSAID and/or the phospholipid, where the amount of NSAID is 1-10fold less than an amount of NSAID needed to illicit the same therapeuticeffect in the absence of the phospholipid. Preferably, the resultingcomposition includes a relatively high concentration of aphospholipid-NSAID association complex. Particularly, the resultingcomposition includes a relatively high concentration of aphosphatidylcholine-NSAID associated complex.

The presence of the phospholipid in the composition of this inventionalso reduces general and specific pathogenic and/or toxicity of NSAIDs.Thus, the phospholipids reduce and/or prevent liver damage due to theadministration of acetaminophen and/or kidney and/or heart damage due tothe administration of other NSAIDs such as ibuprofen or COX2 inhibitors.

General Methods for making the General Compositions

The present invention also relates to a method of preparing acomposition comprising an NSAID in a non-aqueous, fluid carriercomprising the step of combining the NSAID with the carrier to form asolution, a paste, a semi-solid, a dispersion, a suspension, a colloidalsuspension or a mixture thereof, having a relatively high concentrationof the NSAID. Preferably, the carrier comprises aphospholipid-containing bio-compatible oil or a bio-compatible oil and aphospholipid. Preferably, the resulting composition includes arelatively high concentration of a phospholipid-NSAID associationcomplex. Particularly, the resulting composition includes a relativelyhigh concentration of a phosphatidylcholine-NSAID associated complex.

Emulsified Compositions

The present invention also relates to an aqueous emulsion of acomposition including a non-aqueous carrier, where the carrier includesa bio-compatible oil, a phospholipid in an amount sufficient to producea therapeutically beneficial effect and zero to a therapeuticallyeffective amount of an NSAID and when the NSAID is present, the amountof phospholipid is also sufficient to reduce the pathogenic effects ofthe NSAID. The aqueous emulsion can also include bio-compatibleemulsifying agents to maintain the composition in a state of emulsionfor extended periods of time. Preferably, the carrier comprises aphospholipid-containing bio-compatible oil or a bio-compatible oil and aphospholipid. Preferably, the resulting emulsion includes thecomposition having a relatively high concentration of aphospholipid-NSAID association complex. Particularly, the resultingcomposition includes a relatively high concentration of aphosphatidylcholine-NSAID associated complex.

The present invention also relates to an aqueous microemulsion of acomposition including an non-aqueous carrier, where the carrier includesa bio-compatible oil, a phospholipid in an amount sufficient to producea therapeutically beneficial effect and zero to a therapeuticallyeffective amount of a NSAID and when the NSAID is present, the amount ofphospholipid is also sufficient to reduce the pathogenic effects of theNSAID. The aqueous emulsion can also include bio-compatible emulsifyingagents to maintain the composition in a state of emulsion for extendedperiods of time. The aqueous microemulsion can also includebio-compatible emulsifying agents to maintain the composition in a stateof microemulsion for extended periods of time. Preferably, the carriercomprises a phospholipid-containing bio-compatible oil or abio-compatible oil and a phospholipid. Preferably, the resultingemulsion includes the composition having a relatively high concentrationof a phospholipid-NSAID association complex. Particularly, the resultingcomposition includes a relatively high concentration of aphosphatidylcholine-NSAID associated complex.

Method for making Emulsified Compositions

The present invention also relates to a method for preparing an aqueousemulsion of this invention including the step of adding a given amountof a desired non-aqueous composition of this invention to an aqueoussolution in the absence or presence of an emulsifying agent and mixingthe composition and the solution for a time sufficient to form anemulsion, where the emulsifying agent, when present, is present in anamount sufficient to form a stable emulsion.

The present invention also relates to a method for preparing an aqueousmicroemulsion of this invention including the step of adding a givenamount of a desired non-aqueous composition of this invention to anaqueous solution in the absence or presence of an emulsifying agent,mixing the composition and solution for a time sufficient to form anemulsion, and shearing the emulsion under microemulsifying conditions toform a microemulsion, where the emulsifying agent, when present, ispresent in an amount sufficient to form a stable microemulsion.

The reason the emulsifying agent is optional is because the phospholipidthemselves have some emulsifying properties.

Compositions for Treating Inflamation

The present invention also relates to a composition for reducing tissueinflamation including a non-aqueous carrier including a therapeuticallyeffective amount of an NSAID and a sufficient amount of a phospholipidto reduce the pathogenic effects of the NSAID, where the compositionreduces tissue inflammation at an NSAID dose below a dose typicallyrequired to illicit the same therapeutic response in the absence of thephospholipid with decreased mucosal toxicity and/or irritation.

Composition for Treating Platelet Aggregation

The present invention also relates to a composition for reducingplatelet aggregation including a non-aqueous carrier including atherapeutically effective amount of an NSAID and a sufficient amount ofa phospholipid to reduce the pathogenic effects of the NSAID, where thecomposition reduces platelet aggregation at an NSAID dose below a dosetypically required to illicit the same therapeutic response in theabsence of the phospholipid with decreased mucosal toxicity and/orirritation.

Composition for Treating Pyretic Conditions

The present invention also relates to a composition for anti-pyreticactivity including a non-aqueous carrier including a therapeuticallyeffective amount of an NSAID and a sufficient amount of a phospholipidto reduce the pathogenic effects of the NSAID, where the composition hasanti-pyretic activity at an NSAID dose below a dose typically requiredto illicit the same therapeutic response in the absence of thephospholipid with decreased mucosal toxicity and/or irritation.

Composition for Treating Ulcerated and/or Inflammed Tissues

The present invention relates to a composition for treating ulceratedtissues including an aqueous emulsion or microemulsion comprising aphospholipid, a bio-compatible oil and zero to a therapeuticallyeffective amount of an NSAID, where the phospholipid is present in asufficient amount to reduce tissue inflammation and/or ulceration andthe NSAID, when present, reduces inflammation of the affected regions ofthe tissue.

Compositions for Treating Oral Ulcerations and/or Inflammations

The present invention also relates to a mouth wash including an aqueousemulsion or microemulsion comprising a phospholipid, a bio-compatibleoil and zero to a therapeutically effective amount of an NSAID, wherethe phospholipid is present in a sufficient amount to reduce mouthulceration and/or inflammation and the NSAID, when present, reducesinflammation of the affected regions of the mouth.

Compositions for Treating Oral, Esophagus and GI Tract Ulcerations

The present invention also relates to a drinkable medication includingan aqueous emulsion or microemulsion comprising a phospholipid, abio-compatible oil and zero to a therapeutically effective amount of anNSAID, where the phospholipid is present in a sufficient amount toreduce mouth, esophagus, and/or GI tract inflammation and/or ulcerationand the NSAID, when present, reduces inflammation of the affectedregions of the mouth, esophagus and/or GI track.

Composition for Treating Eye Inflammation

The present invention also relates to eye drops including an aqueousemulsion or microemulsion comprising a phospholipid, a bio-compatibleoil and zero to a therapeutically effective amount of an NSAID in anaqueous solution, where the phospholipid is present in a sufficientamount to reduce eye inflammation or irritation and the NSAID, whenpresent, reduces inflammation of the eye associated with uveitis orrelated eye disorders.

Methods for Treating Ulcerated and/or Inflamed Tissues

The present invention also relates to methods for treating inflammatoryand/or ulcerative disorders of the mouth, esophagus, GI tract, eye,and/or other inflamed and/or ulcerated tissue sites via theadministration of an emulsion or microemulsion of this invention.

Composition for Treating Central and/or Peripheral Nerve System Traumas

The present invention also relates to a composition for orally orinternally treating spinal cord, stroke and/or traumatic brain injuries,where the composition includes a non-aqueous carrier including aphospholipid and a therapeutically effective amount of an NSAID or anaqueous solution into which a non-aqueous carrier including aphospholipid and a therapeutically effective amount of an NSAID has beendispersed (e.g., emulsion or microemulsion), where the phospholipidincreases transport of the NSAID across the blood-brain barrier allowingmore NSAID to get to the trauma site and reduce inflammation, whereNSAID reduces inflammation, platelet aggregation, anti-pyretic activityand cell death due to inflammation.

Methods for Treating Central and/or Peripheral Nerve System Traumas

The present invention also relates to methods for treating spinal cord,stroke and/or traumatic brain injuries by injecting a composition ofthis invention either into a vein (i.v. administration), an artery (i.a.administration) or directly into the trauma site (directadministration), where the phospholipid increases transport of the NSAIDacross the blood-brain barrier or other neurogenic barriers allowingmore NSAID to get to the trauma site and reduce inflammation for i.v.and i.a. administration and the phospholipid reduces the pathogeniceffects of the NSAID in all administration formats.

The present invention also relates to a medication for amelioratingsymptoms of spinal chord, stroke and/or traumatic brain injury, wherethe medication includes a relatively high concentration of an NSAID inan oil based or water based carrier including a phospholipid, where theNSAID and the phospholipid form an association complex in themedication, where the composition include a sufficient concentration ofthe NSAID to reduce swelling of the traumatized tissue and a sufficientconcentration of the phospholipid to reduce the pathogenic effects ofthe NSAID on the traumatized tissue.

Composition for Treating Alzheimer's Disease

The present invention also relates to a composition for preventing,treating or ameliorating the symptoms associated with Alzheimer'sdisease including a bio-compatible oil, a phospholipid and atherapeutically effective amount of an NSAID, where the NSAID and thephospholipid act to prevent the onset of the symptoms of Alzheimer'sdisease or ameliorate the symptoms of Alzheimer's disease.

Methods for Treating Alzheimer's Disease

The present invention also relates to a method for preventing, treatingor ameliorating the symptoms associated with Alzheimer's diseaseincluding the step of orally or internally administering a compositionof this invention orally and/or internally according to a treatmentprotocol.

Composition for Treating Incisions

The present invention also relates to a composition for treatingincision to reduce resulting surgically induced local inflammation andpromote healing, including a bio-compatible oil, a phospholipid and atherapeutically effective amount of an NSAID, where the NSAID and thephospholipid act to reduce inflammation and associated symptoms andpromote healing.

Methods for Treating Incisions

The present invention also relates to a method for treating incision toreduce resulting surgically induced local inflammation and promotehealing, including applying a composition including a bio-compatibleoil, a phospholipid and a therapeutically effective amount of an NSAIDto a surgical site during and after surgery, but prior to closing, wherethe NSAID and the phospholipid act to reduce inflammation and associatedsymptoms and promote healing. Preferred treating formulation of thisinvention include spray applications of emulsions or microemulsions orsimilar formulation of the compositions of this invention.

Composition for Ameliorating Ulceration and/or Inflammation Caused byRadio- and/or Chemotherapy

The present invention also relates to compositions for amelioratingtissue ulceration induced by radiotherapy and/or chemotherapy of certaincancers such as mucositis or related condition, where the compositionincludes a bio-compatible oil, a phospholipid and optionally atherapeutically effective amount of an NSAID, where the phospholipid ispresent in an amount sufficient to prevent and/or reduce ulceration orinflammation associated with mucositis and, when an NSAID is present,the phospholipid is present in an amount sufficient not only to preventand/or reduce ulceration or inflammation, but also to ensure that theNSAID does not further exacerbate the condition. Preferably, forchemotherapy, the chemotherapeutic agent is administered with anappropriately formulated composition of this invention. Thus, if thechemotherapeutic agent is administered orally, the agent can be mixedwith an appropriately formulated composition of this invention, providedno adverse interactions occur between the agent and the component of thecompositions of this invention and administered to the patient. Ifadverse interactions between the chemotherapeutic agent and thecomponents of the compositions of this invention occur or if the agentis administered by injection, then the composition of this invention isadministered orally with the chemotherapeutic agent and for a sufficienttime after to prevent or reduce the duration of the mucositis episode.

Methods of Ameliorating Ulceration and/or Inflammation Caused by Radio-and/or Chemotherapy

The present invention also relates to methods for preventing and/ortreating mucositis or other ulcerating condition induced by medicaltreatments such as radiotherapy and/or chemotherapy, where the methodincludes the steps of administering an effective amount of a compositionof this invention including a bio-compatible oil, a phospholipid andoptionally a therapeutically effective amount of an NSAID, where thephospholipid is present in an amount sufficient to prevent and/or reduceulceration and/or inflammation associated with mucositis and, when anNSAID is present, the phospholipid is present in an amount sufficientnot only to prevent and/or reduce ulceration, but also to ensure thatthe NSAID does not further exacerbate the condition, to the affectedarea of the body prior to, concurrent with and/or after radiotherapy orchemotherapy. Preferably, the composition is designed for oraladministration and is given prior to and current with the radio- and/orchemotherapy to prevent and/or treat and/or reduce the duration of amucositis episode.

For oral administration of the compositions of this invention, thecompositions are preferably dispersed in an aqueous solution as smalldroplets in the form of an emulsion, microemulsion or the like. Thesmall droplets can include emulsifying agents, suspending agents andother ingredients commonly found in mouth wash or the like. Thecomposition of the present invention can be used in conjunction with anymouth wash or oral hygiene formulation including those formulationdescribed in U.S. Pat. Nos. 5,407,663, 5,236,699, 5,130,146, 5,085,850,incorporated herein by reference. The composition of this invention canalso be orally administered in the form of a paste, a lozenge, or anyother format commonly used for oral administration. Of course, thecomposition can also be included in capsules, gel capsules or the like.

For topical administration, the compositions of the present inventioncan be in the form of an ointment, a paste, an oil, an emulsion, amicroemulsion, or mixture or combination thereof. Moreover, thecompositions can be mixed with other ingredients commonly used inointments and in the cosmetic industry.

Emulsions

The compositions of the present invention may be prepared and formulatedas emulsions. Emulsions are typically heterogenous systems of one liquiddispersed in another in the form of droplets usually exceeding 0.1 μm indiameter. (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger andBanker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p.199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger andBanker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p.245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker(Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335;Higuchi et al., in Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systemscomprising of two immiscible liquid phases intimately mixed anddispersed with each other. In general, emulsions may be eitherwater-in-oil (w/o) or of the oil-in-water (o/w) variety. When an aqueousphase is finely divided into and dispersed as minute droplets into abulk oily phase the resulting composition is called an water-in-oil(w/o) emulsion. Alternatively, when an oily phase is finely divided intoand dispersed as minute droplets into a bulk aqueous phase the resultingcomposition is called an oil-in-water (o/w) emulsion. Emulsions maycontain additional components in addition to the dispersed phases andthe active drug which may be present as a solution in either the aqueousphase, oily phase or itself as a separate phase. Pharmaceuticalexcipients such as emulsifiers, stabilizers, dyes, and anti-oxidants mayalso be present in emulsions as needed. Pharmaceutical emulsions mayalso be multiple emulsions that are comprised of more than two phasessuch as, for example, in the case of oil-in-water-in-oil (o/w/o) andwater-in-oil-in-water (w/o/w) emulsions. Such complex formulations oftenprovide certain advantages that simple binary emulsions do not. Multipleemulsions in which individual oil droplets of an o/w emulsion enclosesmall water droplets constitute a w/o/w emulsion. Likewise a system ofoil droplets enclosed in globules of water stabilized in an oilycontinuous provides an o/w/o emulsion.

Emulsions are characterized by little or no thermodynamic stability.Often, the dispersed or discontinuous phase of the emulsion is welldispersed into the external or continuous phase and maintained in thisform through the means of emulsifiers or the viscosity of theformulation. Either of the phases of the emulsion may be a semisolid ora solid, as is the case of emulsion-style ointment bases and creams.Other means of stabilizing emulsions entail the use of emulsifiers thatmay be incorporated into either phase of the emulsion. Emulsifiers maybroadly be classified into four categories: synthetic surfactants,naturally occurring emulsifiers, absorption bases, and finely dispersedsolids (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger andBanker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p.199).

Synthetic surfactants, also known as surface active agents, have foundwide applicability in the formulation of emulsions and have beenreviewed in the literature (Rieger, in Pharmaceutical Dosage Forms,Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., NewYork, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms,Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York,N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic andcomprise a hydrophilic and a hydrophobic portion. The ratio of thehydrophilic to the hydrophobic nature of the surfactant has been termedthe hydrophile/lipophile balance (HLB) and is a valuable tool incategorizing and selecting surfactants in the preparation offormulations. Surfactants may be classified into different classes basedon the nature of the hydrophilic group: nonionic, anionic, cationic andamphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Riegerand Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1,p. 285).

Naturally occurring emulsifiers used in emulsion formulations includelanolin, beeswax, phosphatides, lecithin and acacia. Absorption basespossess hydrophilic properties such that they can soak up water to formw/o emulsions yet retain their semisolid consistencies, such asanhydrous lanolin and hydrophilic petrolatum. Finely divided solids havealso been used as good emulsifiers especially in combination withsurfactants and in viscous preparations. These include polar inorganicsolids, such as heavy metal hydroxides, nonswelling clays such asbentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidalaluminum silicate and colloidal magnesium aluminum silicate, pigmentsand nonpolar solids such as carbon or glyceryl tristearate.

A large variety of non-emulsifying materials are also included inemulsion formulations and contribute to the properties of emulsions.These include fats, oils, waxes, fatty acids, fatty alcohols, fattyesters, humectants, hydrophilic colloids, preservatives and antioxidants(Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker(Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335;Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker(Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).

Hydrophilic colloids or hydrocolloids include naturally occurring gumsand synthetic polymers such as polysaccharides (for example, acacia,agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth),cellulose derivatives (for example, carboxymethylcellulose andcarboxypropylcellulose), and synthetic polymers (for example, carbomers,cellulose ethers, and carboxyvinyl polymers). These disperse or swell inwater to form colloidal solutions that stabilize emulsions by formingstrong interfacial films around the dispersed-phase droplets and byincreasing the viscosity of the external phase.

Since emulsions often contain a number of ingredients such ascarbohydrates, proteins, sterols and phosphatides that may readilysupport the growth of microbes, these formulations often incorporatepreservatives. Commonly used preservatives included in emulsionformulations include methyl paraben, propyl paraben, quaternary ammoniumsalts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boricacid. Antioxidants are also commonly added to emulsion formulations toprevent deterioration of the formulation. Antioxidants used may be freeradical scavengers such as tocopherols, alkyl gallates, butylatedhydroxyanisole, butylated hydroxytoluene, or reducing agents such asascorbic acid and sodium metabisulfite, and antioxidant synergists suchas citric acid, tartaric acid, and lecithin.

The application of emulsion formulations via dermatological, oral andparenteral routes and methods for their manufacture have been reviewedin the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman,Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y.,volume 1, p. 199). Emulsion formulations for oral delivery have beenvery widely used because of reasons of ease of formulation, efficacyfrom an absorption and bioavailability standpoint. (Rosoff, inPharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988,Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, inPharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988,Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil baselaxatives, oil-soluble vitamins and high fat nutritive preparations areamong the materials that have commonly been administered orally as o/wemulsions.

Microemulsions

In one embodiment of the present invention, the compositions of thisinvention are formulated as microemulsions. A microemulsion may bedefined as a system of water, oil and amphiphile which is a singleoptically isotropic and thermodynamically stable liquid solution(Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker(Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245).Typically microemulsions are systems that are prepared by firstdispersing an oil in an aqueous surfactant solution and then adding asufficient amount of a fourth component, generally an intermediatechain-length alcohol to form a transparent system. Therefore,microemulsions have also been described as thermodynamically stable,isotropically clear dispersions of two immiscible liquids that arestabilized by interfacial films of surface-active molecules (Leung andShah, in: Controlled Release of Drugs: Polymers and Aggregate Systems,Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215).Microemulsions commonly are prepared via a combination of three to fivecomponents that include oil, water, surfactant, cosurfactant andelectrolyte. Whether the microemulsion is of the water-in-oil (w/o) oran oil-in-water (o/w) type is dependent on the properties of the oil andsurfactant used and on the structure and geometric packing of the polarheads and hydrocarbon tails of the surfactant molecules (Schott, inRemington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.,1985, p. 271).

The phenomenological approach utilizing phase diagrams has beenextensively studied and has yielded a comprehensive knowledge, to oneskilled in the art, of how to formulate microemulsions (Rosoff, inPharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988,Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, inPharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988,Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared toconventional emulsions, microemulsions offer the advantage ofsolubilizing water-insoluble drugs in a formulation of thermodynamicallystable droplets that are formed spontaneously.

Surfactants used in the preparation of microemulsions include, but arenot limited to, ionic surfactants, non-ionic surfactants, Brij 96,polyoxyethylene oleyl ethers, polyglycerol fatty acid esters,tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310),hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500),decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750),decaglycerol sequioleate (S0750), decaglycerol decaoleate (DAO750),alone or in combination with cosurfactants. The cosurfactant, usually ashort-chain alcohol such as ethanol, 1-propanol, and 1-butanol, servesto increase the interfacial fluidity by penetrating into the surfactantfilm and consequently creating a disordered film because of the voidspace generated among surfactant molecules. Microemulsions may, however,be prepared without the use of cosurfactants and alcohol-freeself-emulsifying microemulsion systems are known in the art. The aqueousphase may typically be, but is not limited to, water, an aqueoussolution of the drug, glycerol, PEG300, PEG400, polyglycerols, propyleneglycols, and derivatives of ethylene glycol. The oil phase may include,but is not limited to, materials such as Captex 300, Captex 355, CapmulMCM, fatty acid esters, medium chain (C8-C12) mono, di, andtri-glycerides, polyoxyethylated glyceryl fatty acid esters, fattyalcohols, polyglycolized glycerides, saturated polyglycolized C8-C10glycerides, vegetable oils and silicone oil.

Microemulsions are particularly of interest from the standpoint of drugsolubilization and the enhanced absorption of drugs. Lipid basedmicroemulsions (both o/w and w/o) have been proposed to enhance the oralbioavailability of drugs, including peptides (Constantinides et al.,Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp.Clin. Pharmacol., 1993, 13, 205). Microemulsions afford advantages ofimproved drug solubilization, protection of drug from enzymatichydrolysis, possible enhancement of drug absorption due tosurfactant-induced alterations in membrane fluidity and permeability,ease of preparation, ease of oral administration over solid dosageforms, improved clinical potency, and decreased toxicity (Constantinideset al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm.Sci., 1996, 85, 138-143). Often microemulsions may form spontaneouslywhen their components are brought together at ambient temperature.Microemulsions have also been effective in the transdermal delivery ofactive components in both cosmetic and pharmaceutical applications. Itis expected that the microemulsion compositions and formulations of thepresent invention will facilitate an increased therapeutic response fromthe phospholipids and/or the NSAID-phospholipid combinations in oraladministration via the gastrointestinal tract, as well as improved localcellular therapeutic responses and uptake of the phospholipids and/orthe NSAID-phospholipid combinations through hydrophobic barrier such asbarriers within the gastrointestinal tract, CNS, PNS, vagina, mouth,esophagus, buccal cavity, nasal cavity, sinus cavites and other areas ofadministration.

Microemulsions of the present invention may also contain additionalcomponents and additives such as sorbitan monostearate (Grill 3),Labrasol, and penetration enhancers to improve the properties of theformulation and to enhance the absorption of the phospholipids and/orthe NSAID-phospholipid combinations containing formulations of thepresent invention. Penetration enhancers used in the microemulsions ofthe present invention may be classified as belonging to one of fivebroad categories—surfactants, fatty acids, bile salts, chelating agents,and non-chelating non-surfactants (Lee et al., Critical Reviews inTherapeutic Drug Carrier Systems, 1991, p. 92). Each of these classeshas been discussed above.

Suitable phospholipids for use in this invention include, withoutlimitation, dimyristoyl phosphatidylcholine, distearoylphosphatidylcholine, dilinoleoyl-phosphatidylcholine (DLL-PC),dipalmitoyl-phosphatidylcholine (DPPC), soy phophatidylchloine (Soy-PCor PC_(S)) and egg phosphatidycholine (Egg-PC or PC_(E)). In DPPC, asaturated phospholipid, the saturated aliphatic substitution R₁ and R₂are CH₃—(CH₂)₁₄, R₃ is CH₃ and X is H. In DLL-PC, an unsaturatedphospholipid, R₁ and R₂ are CH₃—(CH₂)₄—CH═CH—CH₂—CH═CH—(CH₂)₇, R₃ is CH₃and X is H. In Egg PC, which is a mixture of unsaturated phospholipids,R₁ primarily contains a saturated aliphatic substitution (e.g., palmiticor stearic acid), and R₂ is primarily an unsaturated aliphaticsubstitution (e.g., oleic or arachidonic acid). In Soy-PC, which inaddition to the saturated phospholipids (palmitic acid and stearic acid)is a mixture of unsaturated phospholipids, [oleic acid, linoleic acidand linolenic acid]. The preferred zwitterionic phospholipid include,without limitation, dipalmitoyl phosphatidylcholine, phosphatidylcholine, or a mixture thereof.

Suitable NSAIDS include, without limitation, Propionic acid drugs suchas Fenoprofen calcium (Nalfon®), Flurbiprofen (Ansaid®), Suprofen.Benoxaprofen, Ibuprofen (prescription Motrin®), Ibuprofen (200 mg. overthe counter Nuprin, Motrin 1B®), Ketoprofen (Orduis, Oruvall®), Naproxen(Naprosyn®), Naproxen sodium (Aleve, Anaprox, Aflaxen®), Oxaprozin(Daypro®), or the like; Acetic acid drug such as Diclofenac sodium(Voltaren®), Diclofenac potassium (Cataflam®), Etodolac (Lodine®),Indomethacin (Indocin®), Ketorolac tromethamine (Acular, Toradol®intramuscular), Ketorolac (oral Toradol®), or the like; Ketone drugssuch as Nabumetone (Relafen®), Sulindac (Clinoril®), Tolmetin sodium(Tolectin®). or the like; Fenamate drugs such as Meclofenamate sodium(Meclomen®), Mefenamic acid (Ponstel®), or the like; Oxicam drugs suchas Piroxicam (Dolibid®), or the like; Salicylic acid drugs such asDiflunisal (Feldene®), Aspirin, or the like; Pyrazolin acid drugs suchas Oxyphenbutazone (Tandearil®), Phenylbutazone (Butazolidin®), or thelike; acetaminophen (Tylenol®), or the like; COX-2 inhibitors such asCelebrex, Vioxx, or the like, or mixtures or combinations thereof.

Suitable bio-compatible emulsifying agent include, without limitation,any ionic or non-ionic emulsifying agent or surfactants approved forhuman or animal consumption or internal use. Exemplary examples includeacetylated monoglycerides, aluminum salts of fatty acids,Arabinogalactan, Bakers Yeast Glycan, Calcium carbonate, Calcium saltsof fatty acids, Carob bean gum (locust bean gum), Curdlan, Diacetyltartaric acid esters of mono- and diglycerides of edible fats or oils,or edible fat-forming fatty acids, Dioctyl sodium sulfosuccinate,Disodium phosphate (X-ref—Sodium phosphate, mono-, di-, & tri-),Ethoxylated mono- and di-glycerides, Eucheuma cottonii extract, Eucheumaspinosum extract, Fatty acids, salts of (aluminum, calcium, magnesium,potassium, and sodium), Food starch esterified with n-octenyl succinicanhydride treated with beta-amylase, Furazolidone, Furcelleran,Furcelleran, salts of ammonium, calcium, potassium, or sodium, Ghattigum, Gigartina extracts, Glyceryl-lacto esters of fatty acids, Hexitololeate, Hydroxylated lecithin, Hydroxypropyl cellulose, Hydroxypropylmethylcellulose, Lactylated fatty acid esters of glycerol and propyleneglycol, Lactylic esters of fatty acids, Lecithin, hydroxylated lecithin,Methyl ethyl cellulose, Mono- & diglycerides of edible fats or oils, oredible fat forming acids, Monoisopropyl citrate, Monosodium phosphatederivatives of mono- & diglycerides of edible fats or oils, or ediblefat-forming fatty acids, Myrj 45 (polyoxyethylene 8-stearate), Ox bileextract, Pectins (including pectin modified), Polyethylene glycol (400)dioleate, Polyglycerol esters of fatty acids, Polyoxyethylene glycol(400) mono- & di-oleates, Polysorbate 60 (Polyoxyethylene (20) sorbitanmonostearate), Polysorbate 65 (Polyoxyethylene (20) sorbitantristearate), Polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate),Potassium salts of fatty acids, Propylene glycol alginate (Propyleneglycol ester of alginic acid), Propylene glycol mono- & di-esters offats & fatty acids, Rapeseed oil, fully hydrogenated, superglycerinated,Sodium acid pyrophosphate, Sodium aluminum phosphate, Sodiumhypophosphite, Sodium lauryl sulfate, Sodium metaphosphate, Sodiummethyl sulfate, Sodium pectinate, Sodium salts of fatty acids, Sodiumstearoyl lactylate, Sodium sulfo-acetate derivatives (mono- &di-glycerides), Sorbitan monooleate, Sorbitan monostearate, Succinylatedmonoglycerides, Succistearin (stearoyl propylene glycol hydrogensuccinate), Sucrose acetate isobutyrate (SAIB), Sucrose fatty acidesters, Sulfated butyl oleate, Trisodium phosphate, Xanthan gum, or thelike or mixtures or combinations thereof.

Suitable neutral lipid include, without limitation, any neutral lipidsuch as the triglyceride. For a partial listing of representativeneutral lipids, such as the triglycerides, reference is specificallymade to U.S. Pat. Nos. 4,950,656 and 5,043,329. Both saturated andunsaturated triglycerides may be employed in the present compositions,and include such triglycerides as tripalmitin (saturated), triolein andtrilinolein (unsaturated). However, these particular triglycerides arelisted here for convenience only, and are merely representative of avariety of useful triglycerides, and is further not intended to beinclusive.

Non-limiting examples of suitable biocompatible, biodegradable polymers,include polylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polyorthoesters,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), poly(amino acids), poly(methyl vinyl ether),poly(maleic anhydride), chitin, chitosan, and copolymers, terpolymers,or higher poly-monomer polymers thereof or combinations or mixturesthereof. The preferred biodegradable polymers are all degraded byhydrolysis.

Typically, the polymers will either be surface erodible polymers such aspolyanhydrides or bulk erodible polymers such as polyorthoesters.Poly(l-lactic acid) (PlLA), poly(dl-lactic acid) (PLA), poly(glycolicacid) (PGA), polycaprolactones, copolymers, terpolymer, higherpoly-monomer polymers thereof, or combinations or mixtures thereof arepreferred biocompatible, biodegradable polymers. The preferredbiodegradable copolymers are lactic acid and glycolic acid copolymerssometimes referred to as poly(dl-lactic-co-glycolic acid) (PLG). Theco-monomer (lactide:glycolide) ratios of the poly(DL-lactic-co-glycolicacid) are preferably between about 100:0 to about 50:50 lactic acid toglycolic acid. Most preferably, the co-monomer ratios are between about85:15 and about 50:50 lactic acid to glycolic acid. Blends of PLA withPLG, preferably about 85:15 to about 50:50 PLG to PLA, are also used toprepare polymer materials.

PLA, PlLA, PGA, PLG and combinations or mixtures or blends thereof areamong the synthetic polymers approved for human clinical use. They arepresently utilized as surgical suture materials and in controlledrelease devices, as well as in other medical and pharmaceuticalapplications. They are biocompatible and their degradation products arelow molecular weight compounds, such as lactic acid and glycolic acid,which enter into normal metabolic pathways. Furthermore, copolymers ofpoly(lactic-co-glycolic acid) offer the advantage of a large spectrum ofdegradation rates from a few days to years by simply varying thecopolymer ratio of lactic acid to glycolic acid.

To enhance bio-degradation of the polymers used in biologicalapplication, the compositions of the present invention can also includethe addition of enzymes that can facilitate the biodegradation of thepolymers used in the composition. Preferred enzymes or similar reagentsare proteases or hydrolases with ester-hydrolyzing capabilities. Suchenzymes include, without limitation, proteinase K, bromelaine, pronaseE, cellulase, dextranase, elastase, plasmin streptokinase, trypsin,chymotrypsin, papain, chymopapain, collagenase, subtilisn,chlostridopeptidase A, ficin, carboxypeptidase A, pectinase,pectinesterase, an oxidoreductase, an oxidase or the like. The inclusionof an appropriate amount of such a degradation enhancing agent can beused to regulate implant duration.

Suitable chemo and/or radiotherapeutic agents (trade names) include,without limitation, platinum complexed, gold (III) complexed, palladiumcomplexes, alitretinoin (Panretin), allopurinol (Zyloprim), altretamine(Hexalen), amifostine (Ethyol), amifostine (Ethyol), amifostine(Ethyol), anastrozole (Arimidex), anastrozole (Arimidex), arsenictrioxide (Trisenox), bexarotene (Targretin), bexarotene (Targretin),bleomycin (Blenoxane), busulfan intravenous (Busulfex), busulfan oral(Myleran), capecitabine (Xeloda), capecitabine (Xeloda), capecitabine(Xeloda), carboplatin (Paraplatin), carboplatin (Paraplatin), carmustinewith Polifeprosan 20 Implant (Gliadel Wafer), celecoxib (Celebrex),chlorambucil (Leukeran), cisplatin (Platinol), cisplatin (Platinol),cisplatin (Platinol), cladribine (Leustatin(2-CdA), cyclophosphamide(Cytoxan), cytarabine liposomal (DepoCyt), daunorubicin liposomal(DanuoXome), daunorubicin daunomycin (Daunorubicin),daunorubicin(daunomycin (Cerubidine), dexrazoxane (Zinecard), docetaxel(Taxotere), docetaxel (Taxotere), docetaxel (Taxotere), doxorubicin(Adriamycin PFS Injection), doxorubicin liposomal (Doxil), doxorubicinliposomal (Doxil), Elliott's B Solution (Elliott's B Solution),epirubicin (Ellence), estramustine (Emcyt), etoposide phosphate(Etopophos), etoposide phosphate (Etopophos), etoposide phosphate(Etopophos), etoposide(VP-16 (Vepesid), etoposide(VP-16 (Vepesid),exemestane (Aromasin), fludarabine (Fludara), fluorouracil(5-FU(Adrucil), gemcitabine (Gemzar), gemcitabine (Gemzar),gemtuzumab-ozogamicin (Mylotarg), goserelin acetate (Zoladex Implant),hydroxyurea (Hydrea Capsules), idarubicin (Idamycin), idarubicin(Idamycin), ifosfamide (IFEX), imatinib mesylate (Gleevec), irinotecan(Camptosar), Irinotecan (Camptosar), irinotecan (Camptosar), letrozole(Femara), letrozole (Femara), leucovorin (Leucovorin), levamisole(Ergamisol), melphalan L-PAM (Alkeran), mesna (Mesnex), methotrexate(Methotrexate), methoxsalen (Uvadex), mitoxantrone (Novantrone),mitoxantrone (Novantrone), paclitaxel (Paxene), paclitaxel (Taxol),paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel(Taxol), paclitaxel (Taxol), paclitaxel (Taxol), paclitaxel (Taxol),pamidronate (Aredia), Pegademase (Adagen (Pegademase Bovine)),pentostatin (Nipent), pentostatin (Nipent), porfimer sodium (Photofrin),porfimer sodium (Photofrin), porfimer sodium (Photofrin), streptozocin(Zanosar), talc (Sclerosol), tamoxifen (Nolvadex), tamoxifen (Nolvadex),tamoxifen (Nolvadex), tamoxifen (Nolvadex), tamoxifen (Nolvadex),tamoxifen (Nolvadex), tamoxifen (Nolvadex), tamoxifen (Nolvadex),temozolamide (Temodar), teniposide VM-26 (Vumon), topotecan (Hycamtin),topotecan (Hycamtin), toremifene (Fareston), tretinoin ATRA (Vesanoid),valrubicin (Valstar), vinorelbine (Navelbine), or mixtures orcombinations thereof. Of course, radiotherapy can also includetraditional radiation treatments.

Although the present invention preferably relates to the use ofunpurified lecithin oils, the present invention can use anybio-compatible oil which contains phospholipids including, withoutlimitation, any human consumable oil containing a phospholipid.

Suitable bio-compatible oils include, without limitation, any oilapproved for human or animal consumption by the FDA including naturaloils such as plant or animal oils or their derivatives or synthetic oilsand especially natural oil that are rich in phospholipids such aslecithin oils from soy beans. Exemplary examples of such oils include,essential oils, vegetable oils an hydrogenated vegetable oils, animaloils such as peanut oil, canola oil, avocado oil, safflower oil, oliveoil, corn oil, soy bean oil, sesame oil, vitamin A, vitamin D, vitaminE, fish oils, or the like.

The formulation or compositions of this invention can also include otherchemicals, such as anti-oxidants (e.g., Vitamin A, C, D, E, etc.), tracemetals and/or polyvalent cations (aluminum, gold, copper, zinc, calcium,etc.), surface-active agents and/or solvents (e.g., propyleneglycol/PPG, dimethy sulfoxide/DMSO, medium chain triglycerides/MCT,etc.), non-toxic dyes and flavor enhancers may be added to theformulation as they are being prepared to improve stability,fluidity/spreadability, permeability, effectiveness and consumeracceptance.

The formulations of the present invention which include a phospholipidpreferably a PC and an NSAID can be used to fill soft gelatin capsulesor hard gelatine or vegicaps for oral administration or used as is, as asolution, a paste, a semi-solid, a dispersion, a suspension, a colloidalsuspension or mixture thereof to be applied topically to inflamed,ulcerated and/or irritated tissue or skin.

One preferred embodiment of this formulation is a lecithin oil basedPC-NSAID composition, which has been tested for GI toxicity. The threeformulations that were tested include lecithin oils combined withaspirin, indomethacin and ibuprofen. In this study, aspirin was combinedwith Phosal 35 SB, a soy lecithin oil, containing 35% PC andintragastrically administered to fasted rats at an aspirin dose of 18mg/kg, where the NSAID:lecithin oil weight ratio was systematicallyvaried from 1:0.5, to 1:1, to 1:2. In addition, other groups of ratsreceived an equivalent dose of aspirin in the absence of the lecithinoil, or an equivalent volume of saline. Forty five minutes later allanimals were intragastrically challenged with 1 ml of 0.6 N HCl, and 15min later, the animals were euthanized and their stomachs opened and thegastric lesions scored by an established method.⁵⁰⁻⁵²

As shown in FIG. 1, the data demonstrated that in contrast to the highnumber of gastric lesions observed in rats administered aspirin alone,rats treated with all three aspirin:lecithin formulations hadsignificantly fewer gastric lesions.

In order to evaluate the gastric toxicity of the non-aspirin NSAIDs,indomethacin and ibuprofen, another ulcer model was employed—GI bleedingwas the endpoint, that as previously described.⁵² In this model, theNSAIDs were intragastrically administered to fasted rats either alone orin combination with the lecithin oil Phosal 35 SB, at a NSAID:lecithinweight ratio of 1:1. Control rats received an equivalent volume ofsaline. To make the rats more sensitive to the GI damaging effects ofthe NSAID all rats also were injected with the nitric oxide (NO)synthase inhibitor, L-NAME (20 mg/kg), three times over the 18-20 hrstudy period, after which the animals were euthanized and the distal 20cm of the GI tract was flushed with 2 ml of saline, and the effusatecollected for hemoglobin analysis—as an index of GI bleeding. Theresults of these experiments are shown in FIGS. 2 and 3, below.

Referring now to FIG. 2, data demonstrated that indomethacin, at a doseof 10 mg/kg, induces a severe increase in GI bleeding that is markedlyand significantly reduced in rats that were intragastricallyadministered an equivalent dose if indomethacin in combination withPhosal 35 SB, at a NSAID:lecithin weight ration of 1:1.

Referring now to FIG. 3, data demonstrated that ibuprofen (which isconsidered one of the least toxic of the conventional NSAIDs in rodentmodel systems), at a dose of 100 mg/kg induces a modest increase in GIbleeding that is significantly reduced in rats that wereintragastrically administered an equivalent dose of ibuprofen incombination with Phosal 35 SB, at a NSAID:lecithin weight ratio of 1:1.

A previously described method was then used to evaluate theanti-inflammatory/analgesic activity of the NSAID-lecithin formulations(in comparison to the NSAIDs alone). This was accomplished be injecting0.1 ml of Complete Freund's Adjuvant (CFA) into the left hindpaw of ratsto induce an acute inflammatory response. Four day later, the rats(which were fasted overnight were intragastrically administered theNSAIDs (either aspirin, indomethacin or ibuprofen) alone on incombination with Phosal 35 SB at a NSAID:lecithin ratio of 1:1 (exceptin the case of aspirin where other ratios were also evaluated). Twohours later, the rats' pain-sensitivity to pressure was measured,employing the Randall-Sellito technique (55). This was accomplished byincrementally increasing the pressure applied to either the inflamedpaw, or the contralateral uninflamed paw, until the animal showed thefirst sign of pain sensation (either vocalization or extension of thedigits on the hindaw being studied), which was noted as the rat's painthreshold. Thus, a low pain threshold indicates that the inflamed paw isvery sensitive to pressure, whereas an increased pain thresholdrepresents low pain sensitivity or analgesia. The results are depictedin FIGS. 4-6.

Referring now to FIG. 4, data demonstrated that aspirin, at a dose of 10mg/kg, had a modest ability to increase the pain threshold of the rats'affected paw, whereas the analgesic activity of an equivalent dose ofaspirin, when administered in combination with lecithin, at all weightratios tested, was significantly enhanced.

Referring now to FIG. 5, data demonstrated that ibuprofen, at a dose of25 mg/kg, has a modest though non-significant, ability to increase thepain pressure threshold of the rats' inflamed paw, whereas the analgesicactivity of an equivalent dose of ibuprofen, when administered incombination with the lecithin oil at a weight ratio of 1:1, wassignificantly enhanced.

Referring now to FIG. 6, data demonstrated that indomethacin, at a doseof 4 mg/kg. The data shows that the paste-like composition provideimproved pain handling activity as compared to unmodified INDO and verymuch improved pain handling activity as compared to the control saline.

NSAIDs and Central and Peripheral Nerves System Trauma and Injury

The process of inflammation is a key component in the progressivepathophysiology associated with both acute, traumatic injuries to theCNS such as spinal cord injury (SCI) [A1] as well as delayed,neurodegenerative diseases such as Alzheimers Disease (AD) [A2]. Theprocess of inflammation is thought to either directly cause, orcontribute to, a progressive deterioration in motor function anddevelopment of chronic pain as commonly observed in SCI and to the lossof memory and cognitive function observed in AD. Recently, the use ofanti-inflammatory drugs has shown efficacy in attenuating tissue lossand functional deficits in a rodent model of traumatic SCI [A3].

Of even greater note, several recent epidemiology studies suggest thatchronic consumption of non-steroidal, anti-inflammatory drugs (NSAIDs)may reduce by up to 50% the risk of AD [A4]. As it is conceivable thateither acute or chronic NSAID treatment strategies may be utilized,depending on the nature of the inflammatory condition, it is crucialthat the NSAIDs are both effective at low doses and well-tolerated withminimal side effects. It is well-established that ˜40% of our populacedevelop gastrointestinal (GI) symptoms in response to chronic NSAIDconsumption which can range from dyspepsia to the induction oflife-threatening episodes of peptic ulceration and bleeding [A5].

In 1995, the PI's laboratory reported that in addition to inhibitingcyclooxygenase (COX) activity, NSAIDs have the capacity to attenuate thesurface hydrophobic barrier of the upper GI tract, most probably bychemically associating with a surface lining of phospholipids [A6].Furthermore, we demonstrated in both laboratory animals and humans thatthe injurious effect of NSAIDs could be prevented if the drugs werechemically associated with the most prominent phospholipid,phosphatidylcholine (PC) as present as either a synthetic species or apurified extract (e.g. from soy lecithin) [A6,A7]. Interestingly, it wasalso demonstrated that in addition to their low GI toxicity, PC-NSAIDsalso possess enhanced therapeutic activity to inhibit fever,inflammation and pain, perhaps attributable to their increased membranepermeability and COX inhibitory activity [A6,A8,A9].

Thus, the composition of this invention attenuate neural inflammationand reduce the pathophysiology associated with several neurologicalconditions including SCI and AD.

Orally-Administered PC-Ibuprofen Reduces the Development ofInflammation-Dependent Hyperalgesia Associated with Peripheral NerveLigation

It has been reported that placement of four loose ligatures of chromicgut sutures around the sciatic nerve will induce severe peripheralneural inflammation of the affected nerve and the induction ofneuropathic pain 2-4 days post surgery, as indicated by a hyperalgesicresponse to pressure or heat applied to the ipsilateral hindpaw[A10,A11]. The effect of PC-NSAID treatment of peripheral neuralinflammation and the reduction of hyperalgesic response using thisinduction technique in rats. This rodent model was used to induce neuralinflammation of either the right or left sciatic nerve using. Shamoperations were performed on the contralateral side. Two dayspost-surgery, the rats were randomly distributed into the followingexperimental groups (12 rats/group); saline control; ibuprofen (15mg/kg); and PC-ibuprofen (equivalent dose of the NSAID). The rats wereadministered the test NSAID formulation b.i.d. for the next two days andseveral behavioral indices of pain sensation were assessed on bothhindpaws before and after the two day dosing period. The behavioralanalyses used to assess efficacy were: guarding behavior of the affectedhindpaw; paw withdrawal latencies to heat; paw withdrawal response tovon Frey hair stimulation; and pain response to the application ofpressure to the hindpaw [A8]. At euthanasia, ligated- and control nerveswere dissected for both macroscopic and histological examination forindices of inflammation. The results of these studies indicate that theanalgesic activity PC-ibuprofen is significantly greater than ibuprofenalone in a model of hindpaw inflammation (induced with Freund'sadjuvant), PC-ibuprofen was also more effective in alleviating painsensitivity due to sciatic nerve ligation, as assessed by measuring thepaw withdrawal response to both von Frey hair stimulation and heat.

Orally-Administered PC-Ibuprofen Decreases Tissue Loss, LocomotorFunction, and Attenuate the Development of Chronic Pain Syndrome in aRat Model of Contusive SCI

Recently, the delivery of a single dose of an anti-inflammatory drug wasshown to reduce the size of a spinal cord lesion in adult rats [A3].These NSAID-treated rats exhibited greater locomotor activity anddecreased symptoms of hyperalgesia and mechanical-allodynia(touch-induced pain), characteristics of neuropathic pain, compared tonon-treated rats. The development of chronic, neuropathic pain is anall-too frequent occurrence following spinal cord injury and can becomea permanent patient burden. The development of a well-tolerated,effective therapy to prevent or attenuate the development of chroniccentral pain is desperately needed. Orally administered PC-NSAIDsreduces tissue damage, improves locomotor outcome, and prevents chronicpain syndrome associated with SCI.

PC-Ibuprofen is more Effective than Ibuprofen at Reducing theDevelopment of Alzheimer's-like Pathophysiology in a Transgenic MouseModel of AD

Recent clinical evidence suggests that NSAIDs may significantly reducethe risk of onset of AD. A major problem is designing treatmentstrategies for AD has been a lack of adequate animal models. Therecently established human β-amyloid-over-expressing Tg2576 mouseprovides a convenient rodent model that demonstrates age-dependentmemory, cognitive, and histopathological deficits including amyloidplaque-formation, microglial-activation, astrocytic reactivity anddystrophic neurites [A19-A21]. Ibuprofen has recently been shown toreduce numbers of amyloid-plaques, dystrophic neurites and activatedmicroglia in the Tg2576 mouse AD model [A21].

Optimization of the Shelf-Life of PC-NSAIDs

The successful commercialization of a PC-NSAID requires a formulationthat remains stable for long periods of time under room temperatureconditions. Although this is not a problem for most NSAIDs likeibuprofen, it remains so for aspirin, that rapidly undergoes hydrolysisto salicylic acid if exposed to water. The formulations of thisinvention based on an NSAID dissolved and/o dispersed in a non-aqueouscarrier such as a lecithin oil or any other bio-compatible oil includinga phospholipid. Because such environments are hydrophobic, they mayresult in enhance aspirin stability in aspirin based formulations.

Experimental Results for Central and Peripheral Nerve System Trauma andInjuries

These experiments demonstrate PC-ibuprofen is a useful treatment ofspinal cord injury (SCI). The results evidence the effects of treatingrats with 25 mg of NSAID/kg body weight, two times a day for 6 weeksafter spinal cord injury (SCI), comparing PC-ibuprofen, ibuprofen andsaline.

Referring to FIGS. 7A and 7B, the graphed data demonstrate that SCI maderats hyperalgesic, as evidenced by a decrease in the pain pressurethreshold of saline-treated SCI rats, using the Randall Sellitotechnique. In contrast, hyperalgesia due to SCI was not seen in SCI ratsthat were treated with either ibuprofen or PC-ibuprofen, withPC-ibuprofen appearing superior to unmodified ibuprofen. This data ispresented in two ways. In FIG. 7A, the data was plotted directly asrecorded (without normalization), while in FIG. 7B, the data values foreach animal are compared to its own baseline preoperative values. Thisgraphical presentation of the data perhaps is most convincing of thebeneficial effects of NSAID administration following SCI.

Referring now to FIG. 8, the superior analgesic activity of PC-ibuprofenin rats with SCI, is also demonstrated in a second behavioral test,where one measures the % of hindpaw responses to stimulation of thehindpaw to fibers (von Frey) hairs having increasing diameters (which isequated to force). Please note that in this case, a lower number isindicative of analgesic, whereas with the Randall Sellito test higherpain pressure threshold values are indicative of analgesia.

Referring now to FIG. 9, evidence that SCI rats treated with ibuprofendo not gain weight over the 6 week study period, in contrast to ratstreated with saline or PC-ibuprofen. This suggestion that rats with SCImay have a mild-toxic reaction to the ibuprofen alone is also indicatedby slight elevations of blood urea nitrogen (evidence of renal toxicity)and lactic dehydrogenase (LDH, evidence of liver toxicity).

Referring now to FIG. 10, evidence that the recovery of motor functionafter SCI, as assessed by the established BBB test, is attenuated inrats treated with unmodified ibuprofen, whereas there was no differencebetween saline and PC-ibuprofen groups in this indice of the recovery ofmotor function.

PC-NSAIDs as Effective Formulation for Treatment of Thrombotic Disorders

The formulations of this invention including a phospholipid such asphosphatidylcholine (PC) and an NSAID, especially aspirin in abio-compatible oil are effective formulation for the treatment ofthrombotic disorders including thrombosis, stroke and myocardialinfarction. In addition to its improved GI safety, PC-aspirin is a morepotent inhibitor of platelet aggregation and thrombogenesis than regularaspirin. Aspirin (ASA) chemically associates with zwitterionicphospholipids forming an association complex that possess the same orenhanced fever, pain, and inflammation reduction activity as compared tonative aspirin, but without aspirin's serious gastrointestinalside-effects of ulceration and bleeding. It is intriguing thatphospholipid-complexed aspirin is more potent than aspirin alone inpreventing thrombus formation in an in vivo model of arterialthrombosis. Therefore, PC-aspirin formulations of this invention inhibitplatelet aggregation and thrombogenesis, reducing the symptoms ofthrombotic disorders.

Thrombotic arterial occlusive diseases such as myocardial infarction(MI) and stroke are the leading cause of death in the U.S. and westernsocieties. According to the American Heart Association, over one millionAmericans will suffer an acute myocardial infarction in the coming year.Drugs that can effectively reduce the incidence of arterial thrombosisare of great clinical importance. As thrombosis is a crucial process inthe initiation and propagation of arterial occlusive disease, there is acompelling reason to develop novel, specific anti-thrombotic drugs.Arterial thrombosis is a complex process involving a series of cellularand biochemical interactions between blood cells, vascular wall andplasma proteins (B1). The blood platelet plays a central role in theseinteractions (B2). It adheres to the damaged vessel wall, undergoescellular activation, secretion and aggregation. The activated plateletaccelerates blood coagulation, and its secreted molecules promotevascular smooth muscle cell proliferation. In view of the central rolethat platelets play in arterial thrombosis, major efforts have been madeover the years to develop anti-thrombotic drugs based on inhibition ofplatelet function (B3). However, few compounds have been clinicallyuseful. In fact, aspirin remains the major drug and the prototype ofanti-platelet agents used clinically due to its efficacy and costconsiderations. It is effective in primary and secondary prevention ofMI and stroke (B4-B7). However, uncertainties remain about aspirin'soptimal therapeutic dose, and more than 40% of patients are unable touse aspirin or even enteric-coated aspirin due to gastrointestinaltoxicity. Of particular relevance is the recent report that even verylow doses of aspirin (10-80 mg) induced gastric erosive injury andbleeding in a significant number of human subjects. This may explain whyat present the largest group of hospital admissions for GI bleedingcurrently are individuals chronically taking low dose aspirin forcardiovascular risk reduction (B8).

The principal mode of action of aspirin and other non-steroidalanti-inflammatory drugs (NSAIDs) has long been known to be through theirability to inhibit prostaglandin synthesis. Two isozymes ofcyclooxygenase, COX-1 and COX-2 have been described and NSAIDs block theactivities of both COX isoforms (B9-B12). Aspirin exerts itsanti-platelet effect by blocking thromboxane A₂ (TXA₂) production byinhibiting COX-1 activity in platelets. However, aspirin also inhibitsthe same enzyme in vascular endothelial cells and thus preventsproduction of prostacyclin (PGI₂) (B13,B14). This inhibition ofendothelial COX, which may enhance the progression of thrombosis oratherosclerosis, is called the “aspirin dilemma”, and is a drawback inits clinical utility. This dilemma has led to the use of low-doseaspirin, suggesting that inhibiting the production of TXA₂ while sparingPGI₂ can provide the optimal anti-thrombotic conditions to reduceplatelet aggregation while maintaining vasodilation. Therefore, afavorable PGI₂ to TXA₂ ratio may have profound implications for thetreatment and prevention of unstable angina, myocardial infarction,transient ischemic attacks, and strokes. With a suitable dose regimen,formulation, and delivery rate, aspirin can possibly prevent plateletTXA₂ generation with a minimal interference with vascular PGI₂production (B15-B17).

NSAID Usage in Treating and/or Preventing Thrombosis

NSAIDs, including aspirin are the most heavily consumed drugs among ourpopulace and their use has increased at an exponential rate over thepast decade, due to the great efficacy of this family of drugs in thetreatment of fever, pain and inflammation (B18). Recent evidence thatindividuals chronically taking aspirin have a lower incidence than thegeneral population in developing cardiovascular diseases (angina,myocardial infarction, thrombosis, and stroke), have resulted in an everincreasing number of people self-medicating with this drug, accountingfor 35-40% of the total annual sales of aspirin (B19). As a consequence,it has been estimated that ˜1% of our population are taking an aspirinon a daily basis. As a consequence the FDA has now approved the use ofaspirin to reduce the risk of stroke, angina and heart attack. However,uncertainties remain about aspirin's optimal therapeutic dose. Onedisturbing aspect of the exponential increase in the usage of NSAIDs,which is expected to continue as the average age of our populationincreases, is that this family of compounds induce serious side-effectsin a significant percentage of users, with the most prevalent beinggastrointestinal bleeding and ulceration (B20). Of particular relevanceis the recent report that even very low doses of aspirin (10-75 mg)induced significant gastric erosive injury and bleeding in humansubjects (B8).

Aspirin dosage can be considerably reduced upon association with azwitterionic phospholipid such as a PC, resulting in a markedimprovement in the drug's benefit:risk ratio. Phospholipid-complexedaspirin selectively inhibited platelet TXA₂ production relative tovascular PGI₂, it is conceivable that these differential effects onplatelet and endothelial COX activities of the phospholipid/aspirincomplex in comparison to the actions of uncomplexed aspirin areimportant for its enhanced anti-thrombotic activity. This observation isfurther supported by the fact that low doses of phospholipid-complexedaspirin in an in vivo model of arterial thrombosis, prevented thrombusformation and vascular occlusion throughout the duration of theexperiment, whereas at this sub-threshold dose aspirin alone failed toprevent thrombus formation and the vessel occluded within an hour. Italso should be emphasized that an additional benefit of PC-aspirin isthat it produces significantly less gastric mucosal injury than regularaspirin and therefore the development of PC-aspirin complex as aneffective anti-thrombotic agent without gastrointestinal side effectswill have broad, cost effective clinical applications.

Results of Principal Investigator:

In 1995, Lichtenberger and his associates (B21) reported in rats thatthe acute GI injurious actions of orally administered aspirin and anumber of other NSAIDs (including diclofenac, indomethacin, andnaproxen) could be markedly reduced if the drug was pre-associated withdipalmitoyl phosphatidylcholine (DPPC), a synthetic PC, or a purifiedextract of soy lecithin. Recently, the inventor reported (B22) theresults of a pilot double blind crossover clinical study, in whichsixteen healthy volunteers were orally administered either aspirin oraspirin complexed to PC (650 mg t.i.d.) over a 4-day study period, andmucosal injury was assessed by video-endoscopy. As shown in FIG. 11, thePC-aspirin complex significantly reduced the number of gastric erosionsby 70% in susceptible individuals in comparison to an equivalent dose ofunmodified aspirin. This reduction in gastric toxicity did not relate toan alteration in the COX inhibitory activity of the drug, as bothaspirin and PC-aspirin had an equivalent ability to inhibit antral COXactivity by >85% as shown in FIG. 12.

The inventor's laboratory also reported (B23) that the therapeuticactivity of aspirin to inhibit fever, inflammation, and pain in rats isconsistently enhanced when the NSAID is administered in chemicalassociation with a PC, with its therapeutic potency increasing 5-10 foldover the unmodified NSAID. Additional studies using rodent models ofarthritis have also produced confirmatory evidence that a NSAID'spotency to inhibit joint inflammation and pain is enhanced if the drugwas intragastrically administered in chemical association with a PC.

Ex vivo animal studies of the effects of phospholipid-aspirin complex(containing equimolar concentration of the two agents) on the ability toproduce TXA₂ and PGI₂ in platelets and vascular tissue respectively wereinvestigated. Rats were intragastrically administered either unmodifiedor DPPC-associated aspirin (20 mg/kg dose), and after 30 minutes, bloodwas drawn, platelet-rich plasma was prepared, and aggregation wasinduced by arachidonic acid. There was a reduction in TXB₂ (a stablemetabolite of TXA₂) production in the platelets of rats individuallytreated with unmodified aspirin or DPPC-aspirin as compared to salinecontrol. PC-aspirin, further suppressed the production of TXB₂ as shownin FIG. 13A.

This ex vivo approach was then used to measure vascular (endothelial)PGI₂. Abdominal aorta excised one hour after drug administration wasevaluated for its ability to produce 6-keto PGF_(1α) (a stablemetabolite of PGI₂) by incubating it with arachidonic acid (AA, 25 mM).As shown in FIG. 13B, aspirin significantly inhibited the production of6-keto PGF_(1a), whereas the DPPC alone and DPPC complexed with ASA hadno effect, as compared to control. It is, therefore, possible to achieveselective inhibition of platelet cyclooxygenase and preserve vascularprostacyclin biosynthesis by the administration of PC-aspirin.

The anti-thrombotic effect of aspirin with or without PC was thenevaluated in an in vivo model of arterial thrombogenesis. According tothe protocol (B24), the left carotid artery of an anesthetized rabbitwas subjected to anodal current to the point where mean carotid bloodflow velocity was increased by 50% above control values, whichcorresponds to 50% occlusion of the vessel by the formed thrombus. Atthis point the current was discontinued and the test drugs intravenouslyadministered as blood flow was monitored over the next 2-3 hours. It canbe appreciated from FIG. 14A that carotid artery blood flow velocitydropped to zero (indicative of complete thrombus occlusion of thevessel) in <60 min in control rabbits treated with either saline orphospholipid alone (mean time until closing=40±17). In contrast, rabbitsadministered unmodified aspirin, within a 5-20 mg/kg dose range, had novessel occlusion throughout the duration of the 2-3 hr experiment (datanot shown). Interestingly, when the dose of aspirin was reduced to 2.5mg/kg, it was observed that aspirin complexed with phospholipid wasstill effective in preventing thrombus formation (>180 min afteradministration of the complex) whereas aspirin alone (at thissub-threshold dose) failed to prevent thrombus formation and the vesseloccluded within 61±15 minutes (n=4) as shown in FIG. 14A. Moreover, theweight of the thrombus formed in rabbits given the aspirin-phospholipidcomplex at the 2.5 mg/kg dose was significantly smaller than thosetreated with either native aspirin, saline or phospholipid alone asshown in FIG. 14B.

6-keto PGF_(1α) (a metabolite of PGI₂) and TXA₂ concentrations was alsomeasured in the affected carotid arteries. In saline control rabbits,the ratio of PGI₂ to TXA₂ in affected arteries—where the thrombus hadformed, was significantly lower (because of increased TXB₂ production)than the unaffected (normal) carotid arteries—where no thrombus wasgenerated. This PGI₂ to TXA₂ ratio improved slightly when the rabbitswere treated with aspirin (2.5 mg/kg) or phospholipid alone, but notenough to block the thrombus formation. In contrast the PGI₂/TXA₂ ratioin rabbits, which received the same dosage of PC-aspirin, improvedsignificantly and was not significantly different from the ratiodetermined in the normal arteries (not exposed to anodal current) ofsaline-treated rabbits as shown in FIG. 14C.

PC-Acetaminophen Formulations

FIG. 15 graphically depicts data indicating that a 1:2 ratio ofacetaminophen (Tylenol):P35 SB provides rats with protection from liverinjury as indicated by elevations of the liver enzyme aspartatetransaminase (AST), 24 hrs after fasted Sprague Dawley rats are orallychallenged with either Tylenol alone or the above Tylenol:P35 SBcombinations. The data shows that by using several statistical tests itappears that AST levels are significantly elevated in the Tylenoltreated rats vs saline control values, but not in the rats administeredthe Tylenol:P35 SB combination at a 1:2 wt ratio.

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All references cited herein are incorporated by reference. While thisinvention has been described fully and completely, it should beunderstood that, within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described. Although theinvention has been disclosed with reference to its preferredembodiments, from reading this description those of skill in the art mayappreciate changes and modification that may be made which do not departfrom the scope and spirit of the invention as described above andclaimed hereafter.

I claim:
 1. A method for producing a pharmaceutical composition that isa NSAID-in-oil suspension, said method comprising admixing a NSAID inpowder form into a lecithin oil to obtain a NSAID-in-oil suspension,such that the NSAID (i) associates with phospholipids in the lecithinoil and (ii) is present in a therapeutically effective amount and theNSAID-in-oil suspension has a gastrointestinal toxicity that is reducedrelative to the NSAID alone, wherein said NSAID is selected from thegroup consisting of aspirin, indomethacin and ibuprofen.
 2. The methodof claim 1, wherein the NSAID is aspirin.
 3. The method of claim 1,wherein the weight ratio of NSAID to lecithin oil present in theNSAID-in-oil suspension is from about 4:1 to about 1:4.
 4. The method ofclaim 3, wherein the weight ratio of NSAID to lecithin oil is about 1:1.5. The method of claim 1, wherein said lecithin oil comprises about 35%phosphatidylcholine.
 6. The method of claim 2, wherein said lecithin oilcomprises about 35% phosphatidylcholine.